Injectable capsaicin with tricyclic antidepressant adjunctive agent

ABSTRACT

Disclosed in certain embodiments is a method for relieving pain at a site in a human or animal in need thereof, comprising administering by injection or infiltration, a dose of a capsaicinoid and coadministering a tricyclic antidepressant.

This application claims the benefit of U.S. Provisional PatentApplication No. 60/434,453, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,530, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,500, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,828, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,452, filed Dec. 18, 2002, U.S. Provisional PatentApplication No. 60/434,501, filed Dec. 18, 2002, and U.S. ProvisionalPatent Application No. 60/461,164, filed Apr. 8, 2003, the disclosuresof which is hereby incorporated by reference in their entirety.

FIELD OF THE INVENTION

This application is directed to compositions and methods for relievingpain at a specific site, for example, associated with inflammation ofjoints, tendons, nerves, muscle, and other soft tissues, nerve injuryand neuropathies, and pain from tumors in soft tissues or bone.

BACKGROUND OF THE INVENTION

Capsaicin, a pungent substance derived from the plants of the solanaceaefamily (hot chili peppers) has long been used as an experimental toolbecause of its selective action on the small diameter afferent nervefibers C-fibers and A-delta fibers that are believed to signal pain.From studies in animals, capsaicin appears to trigger C-fiber membranedepolarization by opening cation channels permeable to calcium andsodium. Recently one of the receptors for capsaicin effects has beencloned. Capsaicin can be readily obtained by ethanol extraction of thefruit of capsicum frutescens or capsicum annum. Capsaicin is known bythe chemical nameN-(4-hydroxy-3-methoxybenzyl)-8-methylnon-trans-6-enamide. Capsaicin ispractically insoluble in water, but freely soluble in alcohol, ether,benzene and chloroform. Therapeutically capsaicin has been used as atopical analgesic. Capsaicin is available commercially as Capsaicin USPfrom Steve Weiss & Co., 315 East 68^(th) Street, New York, N.Y. 10021and can also be prepared synthetically by published methods. SeeMichalska et al., “Synthesis and Local Anesthetic Properties ofN-substituted 3,4-Dimethoxyphenethylamine Derivatives”, Diss Pharm.Pharmacol., Vol. 24, (1972), pp. 17-25, (Chem. Abs. 77: 19271a),discloses N-pentyl and N-hexyl 3,4-dimethoxyphenylacetamides which arereduced to the respective secondary amines.

Capsaicin is listed in the pharmacopoeias of the United Kingdom,Australia, Belgium, Egypt, Germany, Hungary, Italy, Japan, Poland,Portugal, Spain, and Switzerland and has previously been listed in theUnited States Pharmacopoeia and the National Formulary. The FDA proposedmonographs on analgesic drug products for over-the-counter (OTC) humanuse. These include capsaicin and capsicum preparations that are regardedas safe and effective for use as OTC external analgesics. Capsaicin isthe only chemical entity of Capsicum recognized by the FDA. Capsaicin(USP) contains not less than 110% total capsaicinoids which typicallycorresponds to 63% pure capsaicin. USP capsaicin is trans-capsaicin(55-60%) and also contains the precursors dihydrocapsaicin andnordihydrocapsaicin.

Capsaicin mediated effects include: (i) activation of nociceptors inperipheral tissues; (ii) eventual desensitization of peripheralnociceptors to one or more stimulus modalities; (iii) cellulardegeneration of sensitive A-delta and C-fiber afferents; (iv) activationof neuronal proteases; (v) blockage of axonal transport; and (vi) thedecrease of the absolute number of nociceptive fibers without affectingthe number of non-nociceptive fibers.

The dosage forms of capsaicin which have been most widely studiedclinically are capsaicin containing creams (Zostrix, Zostrix-HP, andAxsain). These products have been examined in a broad spectrum ofpainful conditions including osteoarthritis. However the efficacy oftopically administered capsaicin in arthritis in general has proven tobe limited.

Prior publications describe topical administration of capsaicin for thetreatment of various conditions. For example, U.S. Pat. No. 4,997,853(Bernstein) describes methods and compositions utilizing capsaicin as anexternal analgesic. U.S. Pat. No. 5,063,060 (Bernstein) describescompositions and methods for treating painful, inflammatory or allergicdisorders. U.S. Pat. No. 5,178,879 (Adekunle, et al) describes methodsfor preparing a non-greasy capsaicin gel for topical administration forthe treatment of pain. U.S. Pat. No. 5,296,225 (Adekunle, et al.)describes indirect methods of treating orofacial pain with topicalcapsaicin. U.S. Pat. No. 5,665,378 (Davis, et al.) describes transdermaltherapeutic formulations comprising capsaicin, a nonsteroidalanti-inflammatory agent and pamabrom for the treatment of pain. U.S.Pat. No. 6,248,788 (Robbins, et al.) describes administration of 7.5%capsaicin cream in combination with marcaine epidural injections inpatients suffering from long-term persistent foot pain. U.S. Pat. No.6,239,180 (Robbins) describes combining capsaicin loaded patches withlocal anesthesia to treat peripheral neuropathy. The use of topicalcapsaicin has also been described in the art to treat conditions asdiverse as post mastectomy pain syndrome (Watson and Evans, Pain 51:375-79 (1992)); painful diabetic neuropathy (Tandan et al., DiabetesCare 15: 8-13 (1992)); The Capsaicin Study Group, Arch Intern Med 151:2225-9 (1991); post-herpetic neuralgia (Watson et al., Pain 33: 333-40(1988)), Watson et al., Clin. Ther. 15: 510-26 (1993); Bernstein et al.,J. Am. Acad Dermatol 21: 265-70 (1989) and pain in Guillian-Barresyndrome (Morganlander et al., Annals of Neurology 29:199 (1990)).Capsaicin has also been used in the treatment of osteoarthritis (Deal etal., Clin Ther 13: 383-95 (1991); McCarthy and McCarthy, J. Rheumatol19: 604-7 (1992); Altman et al., Seminars in Arthritis and Rheumatism23: 25-33 (1994). In addition, U.S. Pat. No. 4,599,342 (LaHann)describes oral and subcutaneous or intramuscular administration of acombination of capsaicin or a capsaicin analog with an opioid analgesic.U.S. Pat. No. 4,313,958 (LaHann) describes intrathecal, epidural,intramuscular, intravenous, intraperitoneal and subcutaneousadministration of capsaicin utilizing a “stair-step” dosing pattern.

Humans have long been exposed to dietary sources of capsaicin-containingspices and to topical preparations used for a variety of medicalindications. This vast experience has not revealed significant orlasting adverse effects of capsaicin exposure. The recent determinationof capsaicin's potential therapeutic effects on unmyelinated sensoryafferent nerve fibers require diligent consideration of this compoundfor further pharmaceutical development.

Because of capsaicin's ability to desensitize nociceptors in peripheraltissues, its potential analgesic effects have also been assessed invarious clinical trials. However, since the application of capsaicinitself frequently causes burning pain and hyperalgesia apart from theneuropathic pain being treated, patient compliance has been poor and thedrop out rates during clinical trials have exceeded fifty percent. Thespontaneous burning pain and hyperalgesia are believed to be due tointense activation and temporary sensitization of the peripheralnociceptors at the site of capsaicin application. This activation andsensitization occur prior to the desensitization phase. The activationphase could be a barrier to use of capsaicin because of the painproduced.

It would therefore be advantageous to provide methods and compositionsincluding capsaicin or capsaicin analogues thereof with effectiveconcentrations to cause an analgesic effect without the side effectsnormally associated with the use of capsaicin.

OBJECTS AND SUMMARY OF THE INVENTION

It is an object of the present invention to provide compositions andmethods for providing pain relief in humans and animals by administeringan injectable or implantable dose of capsaicin or capsaicin analogue toa site for the treatment of acute or chronic pain, nociceptive andneuropathic pain, pre- and post-operative pain, cancer pain, painassociated with neurotransmitter dysregulation syndromes and orthopedicdisorders.

It is another object of the invention to provide compositions andmethods for attenuating pain at a discrete site in a human or animal viathe administration of a capsaicinoid via injection or implantation atthe discrete site.

It is another object of the present invention to provide compositionsand methods for relieving pain at an intra-articular site or at a bodyspace by administering an injectable or implantable single dose ofcapsaicin or capsaicin analogue to the intra-articular site or bodyspace.

It is an object of the present invention to provide compositions andmethods for providing pain relief in humans and animals by administeringvia infiltration a dose of capsaicin or capsaicin analogue to a surgicalsite or open wound for the treatment of acute or chronic pain,nociceptive and neuropathic pain, pre- and post-operative pain, cancerpain, pain associated with neurotransmitter dysregulation syndromes andorthopedic disorders.

It is another object of the present invention to provide compositionsand methods for attenuating pain at a surgical site in a human or animalvia the administration of a capsaicinoid via infiltration at thesurgical site.

It is another object of the present invention to provide compositionsand methods for attenuating pain at an open wound in a human or animalvia the administration of a capsaicinoid via infiltration at the openwound.

It is a further object of the invention to provide compositions andmethods for treatment of sports-related injuries utilizing injectable orimplantable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treatment of pain associated with median sternotomyutilizing infiltratable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treatment of pain associated with mastectomy utilizinginfiltratable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treatment of pain associated with orthopedic surgicalprocedures utilizing infiltratable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treatment of orthopedic disorders or injuries utilizinginjectable or implantable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating acute traumatic pain utilizing injectable,implantable or infiltratable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating neuropathic pain utilizing injectable, implantableor infiltratable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating nociceptive pain utilizing injectable, implantableor infiltratable capsaicinoids.

It is a further object of the invention to provide compositions andmethods for treating neurotransmitter-dysregulation syndromes utilizinginjectable, implantable or infiltratable capsaicinoids.

In accordance with the above objects and others, the invention isdirected in part to a method for attenuating or relieving pain at a sitein a human or animal in need thereof, comprising administering viainjection, implantation or infiltration at a discrete site, a surgicalsite, or an open wound in a human or animal in need thereof a singledose of capsaicin in an amount effective to denervate the discrete sitewithout eliciting an effect outside the discrete location and toattenuate pain emanating from said site, the dose ranging from about 1μg to about 5,000 μg capsaicin or a therapeutically equivalent dose of acapsaicinoid other than capsaicin when said dose is injected orinfiltrated into a discrete site in the human or animal, and the doseranging from about 1 μg to about 15,000 μg capsaicin or atherapeutically equivalent dose of a capsaicinoid other than capsaicinwhen said dose is infiltrated into a surgical site or an open wound. Inother words, the term “capsaicinoid” is meant to encompass formulationswhere the drug is capsaicin, a capsaicinoid other than capsaicin, or amixture of capsaicin with one or more other capsaicinoids (the totalamount of all capsaicinoid drug being based on a therapeuticallyequivalent dose to dose from about 1 μg to about 5,000 μg capsaicin forinjection or infiltration, and the total amount of all capsaicinoid drugbeing based on a therapeutically equivalent dose to dose from about 1 μgto about 15,000 μg capsaicin for infiltration).

The present invention is further directed in part to a method forattenuating or relieving pain at a site in a human or animal in needthereof, comprising administering at a discrete painful site in a humanor animal in need thereof a single injectable or implantable dose of acapsaicinoid in an amount effective to denervate said discrete sitewithout eliciting an effect outside the discrete location and toattenuate pain emanating from said site, said effective dose being fromabout 1 μg to about 5,000 μg of capsaicin or a therapeuticallyequivalent dose of a capsaicinoid other than capsaicin. In certainpreferred embodiments, the dose of capsaicin for injection orimplantation is from about 10 to about 3000 μg, and preferably fromabout 300 to about 1200 μg. In preferred embodiments, the dose ofcapsaicinoid is administered in a pharmaceutically and physiologicallyacceptable vehicle for injection or implantation, which may optionallyfurther include one or more pharmaceutical excipient. In certainpreferred embodiments, a local anesthetic may be administered prior toor concurrently with said dose of capsaicinoid in an amount and locationeffective to attenuate an initial hyperalgesic effect of theadministered dose of capsaicinoid. The local anesthetic may beadministered, e.g., by direct injection into the site where said dose ofcapsaicinoid is administered, or as a proximal, regional, somatic, orneuraxial block. General anesthesia may be used, if necessary. The doseof capsaicinoid may be injected or implanted subcutaneously,intramuscularly, itrathecally, epidurally, intraperitoneally, caudallyintradermally or intracutaneously, intercostally at a single nerve,intra-articularly, intrasynovially, intraspinally, intra-arterially orinto body spaces. Intra-articular administration of the formulations ofthe invention may be, e.g., into a joint selected from the groupconsisting of knee, elbow, hip, sternoclavicular, temporomandibular,carpal, tarsal, wrist, ankle, intervertebral disk, ligamentum flavum andany other joint subject to pain.

In certain other embodiments of the present invention, there is provideda method for attenuating or relieving pain at a surgical site or openwound in a human or animal in need thereof, comprising administering viainfiltration at a surgical site or open wound in a human or animal inneed thereof a single dose of capsaicin in an amount effective todenervate the surgical site or open wound without eliciting an effectoutside the surgical site or open wound, the dose ranging from about 1μg to about 15,000 μg. In certain preferred embodiments, the effectivedose of capsaicinoid is from about 500 to about 15,000 μg capsaicin, orfrom about 600 to about 10,000 μg capsaicin, or a therapeuticallyequivalent dose of a capsaicinoid other than capsaicin. In certainpreferred embodiments, the dose of capsaicinoid is administered in apharmaceutically acceptable vehicle for infiltration in a volume fromabout 0.1 to about 1000 ml. In certain preferred embodiments, the doseof capsaicinoid is administered in a pharmaceutically acceptable vehiclefor infiltration in a volume from about 1 ml to about 100 ml. In otherfurther preferred embodiments, the dose of capsaicinoid is administeredin a pharmaceutically acceptable vehicle for infiltration in a volumefrom about 5 ml to about 30 ml. In certain preferred embodiments wherethe capsaicinoid is infiltrated into a surgical site or an open wound,the method further comprises administering a local or general anestheticprior to or concurrently with said dose of capsaicinoid. The dose oflocal anesthetic may be, e.g., an amount and location effective toattenuate an initial hyperalgesic effect of said administered dose ofcapsaicinoid. The local anesthetic may be administered by infiltrationto the surgical or wound site. In certain preferred embodiments, theadministration of capsaicinoid at the site provides attenuation of painin proximity to the surgical or wound site for at least about 48 hours,and preferably for at least about one week.

The present invention is further directed in part to a method forattenuating or relieving pain at a surgical site or open wound in ahuman or animal in need thereof, comprising administering at a surgicalsite or open wound in a human or animal in need thereof a singleinfiltratable dose of a capsaicinoid in an amount effective to denervatesaid surgical site or open wound without eliciting an effect outside thesurgical site or open wound, said effective dose being from about 1 μgto about 15,000 μg of capsaicin or a therapeutically equivalent dose ofa capsaicinoid other than capsaicin.

The dose of capsacinoid administered by infiltration into the surgicalsite or open wound may be administered directly onto the tissue, muscleor bone. In other embodiments, the dose of capsaicinoid may beadministered intra-articularly intra-sternally, intrasynovially,intra-bursally or into body spaces. Intra-articular administration ofthe formulations of the invention may be, e.g., into a joint selectedfrom the group consisting of knee, elbow, hip, sternoclavicular,temporomandibular, carpal, tarsal, wrist, ankle, intervertebral disk,ligamentum flavum and any other joint subject to pain.

The invention is further directed in part to a method of treating acutetraumatic pain associated with an injury, comprising injecting acapsaicinoid in a physiologically compatible vehicle through the skin ofa patient in proximity to an injury, said dose of capsaicinoid beingsufficient to attenuate the dull, aching pain associated with C-fibersin proximity to the injury and such that the patient continues to havesensation in proximity to the injury and without affecting sharpprotective pain associated with A-delta fibers in proximity to the site,the dose of capsaicinoid being therapeutically equivalent to a dose ofcapsaicin in an amount from about 300 to about 1500 μg and beingeffective to attenuate dull, aching pain in proximity to the injury forat least about 48 hours.

The invention is further directed in part to a method of treating acutetraumatic pain associated with surgery or open wound injury, comprisingadministering via infiltration a capsaicinoid in a physiologicallycompatible vehicle at the surgical site or open wound of a patient, saiddose of capsaicinoid being sufficient to attenuate the dull, aching painassociated with C-fibers in proximity to the surgical site or open woundand such that the patient continues to have sensation in proximity tothe surgical site open wound and without affecting sharp protective painassociated with A-delta fibers in proximity to the surgical site or openwound, the dose of capsaicinoid being therapeutically equivalent to adose of capsaicin in an amount from about 600 to about 15,000 μg andbeing effective to attenuate dull, aching pain in proximity to thesurgical site or open wound for at least about 48 hours.

In certain preferred embodiments, the capsaicinoid is capsaicin itself.In more preferred embodiments, the capsaicinoid comprisestrans-capsaicin. In most preferred embodiments, the capsaicinoid is atleast about 97% trans-capsaicin.

The single injectable, implantable or infiltratable dose of acapsaicinoid administered at a discrete site, surgical site or openwound in accordance with the present invention is preferably in anamount effective to a) produce a selective, highly-localized destructionor incapacitation of C-fibers and/or A-delta fibers in a discrete,localized area responsible for the initiation of pain for the purpose ofreducing or eliminating pain arising from a discrete locus, and b)minimize potential adverse consequences of C-fiber and/or A-deltaactivation and or damage outside of the locus of pain.

The present invention is also directed to an injectable or implantablepharmaceutical composition for attenuating pain at a site in a human oranimal in need thereof, consisting essentially of from 1 μg to 5000 μgof a capsaicinoid comprising trans-capsaicin and a pharmaceuticallyacceptable vehicle for injection or implantation. In certain preferredembodiments, the dose of trans-capsaicin ranges from about 10 μg toabout 3000 μg, from about 300 μg to about 1500 μg, or preferably fromabout 400 μg to about 1200 μg.

The present invention is also directed to an infiltratablepharmaceutical composition for attenuating pain at a surgical site oropen wound in a human or animal in need thereof, consisting essentiallyof from 1 μg to 15,000 μg of a capsaicinoid comprising trans-capsaicinand a pharmaceutically acceptable vehicle for infiltration. In certainpreferred embodiments, the dose of trans-capsaicin ranges from about 600μg to about 15,000 μg, from about 600 μg to about 10,000 μg, orpreferably from about 1,000 μg to about 10,000 μg.

In order that the invention described herein may be more fullyunderstood, the following definitions are provided for the purposes ofthis disclosure:

The term “injection” shall mean administration of capsaicin to adiscrete site through the skin of a human or animal.

The term “implantation” shall mean administration of capsaicin to adiscrete site by embedding the dose of capsaicin into the skin, tissue,muscles, tendons, joints, or other body parts of a human or animal.

The term “infiltration” or “infiltratable” shall mean administrationinto a discrete surgical site or open wound in a human or animal.

As used herein, the term “capsaicinoid” means capsaicin, capsaicin USPand purified capsaicin, capsaicin analogues and derivatives thereof(collectively referred to as capsaicinoids in this specification andappended claims) that act at the same pharmacologic sites, e.g., VR1, ascapsaicin, unless otherwise specified.

Acute pain shall mean any pain that presents with a rapid onset followedby a short, severe course, e.g., headache, pain associated with cancer,fractures, strains, sprains, and dislocations of bones, joints,ligaments and tendons.

Chronic pain shall mean pain that lasts for a long period of time or ismarked by frequent recurrence, e.g., pain associated with terminalillnesses, arthritis, autoimmune diseases; or neuropathic pain caused bydegenerative diseases such as diabetes mellitus or spinal degeneration,or resulting from neural remodeling following traumatic injury orsurgery.

As used herein, the term “local anesthetic” means any drug or mixture ofdrugs that provides local numbness and/or analgesia.

By co-administration it is meant either the administration of a singlecomposition containing both the capsaicin and an additionaltherapeutically effective agent(s), e.g., local anesthetic or phenol, orthe administration of a capsaicin and the additional therapeuticallyeffective agent(s) as separate compositions within short enough timeperiods that the effective result is equivalent to that obtained whenboth compounds are administered as a single composition.

BRIEF DESCRIPTION OF THE DRAWINGS

The following drawings are illustrative of embodiments of the inventionand are not meant to limit the scope of the invention as encompassed bythe claims.

FIG. 1 is a graph displaying the plasma concentration of the 10 μg, 100μg and 300 μg doses of capsaicin administered to study subjects enteredinto the Osteoarthritis Safety Study exemplified in Example 1.

FIG. 2 is a graph displaying the percent reduction in VAS score comparedto baseline in study subjects entered into the Osteoarthritis SafetyStudy exemplified in Example 1.

FIG. 3 is a graph displaying the NRS Pain Score in study subjectsentered into the Osteoarthritis Efficacy Study exemplified in Example 2.

FIG. 4 is a graph displaying a comparison of VAS Pain Score betweensubjects entered into the Bunionectomy Efficacy study exemplified inExample 3.

FIG. 5 is a graph displaying a comparison of the percent of subjectsentered in to the Bunionectomy Efficacy study exemplified in Example 3requiring rescue medication.

DETAILED DESCRIPTION OF THE INVENTION

The compositions and methods disclosed herein can be used for treatingpain at a specific site with an effective amount of capsaicin orcapsaicin analogue, hereinafter collectively referred to as“capsaicinoids”. In one preferred embodiment, the methods involveadministration of an effective amount of capsaicinoid to a site in ahuman or animal for relieving pain at the site.

In another embodiment, the methods involve providing anesthesia to thesite where the capsaicinoid is to be administered, and thenadministering an effective amount of capsaicinoid to the site. Theanesthesia can be provided directly to the site, or at a remote sitethat causes anesthesia at the site where the capsaicinoid is to beadministered. For example, epidural regional anesthesia can be providedto patients to which the capsaicinoid is to be administered at a sitelocated from the waist down. Alternatively, a local anesthetic may beadministered as a regional block, a proximal block, a somatic block, ora neuraxial block. The anesthetic may be administered as a generalanesthetic, as a spinal block, as an epidural block, or as a nerveblock. Preferably, in the embodiments in which a local anesthetic isadministered, the local anesthetic is administered prior toadministration of the capsaicinoid, such that the local anesthetic hasprovided temporary anesthesia to the area to be treated with thecapsaicinoid.

Examples of local anesthetic agents which can be used includebupivacaine, ropivacaine, dibucaine, procaine, chloroprocaine,prilocalne, mepivacaine, etidocaine, tetracaine, lidocaine, andxylocaine, and mixtures thereof and any other art-known pharmaceuticallyacceptable local anesthetic. The local anesthetic can be in the form ofa salt, for example, the hydrochloride, bromide, acetate, citrate,carbonate or sulfate. More preferably, the local anesthetic agent is inthe form of a free base. Preferred local anesthetic agents include,e.g., bupivacaine. For bupivacaine, the free base provides a slowerinitial release and avoids an early “dumping” of the local anesthetic atthe infiltration site. Other local anesthetics may act differently.Local anesthetic agents typically administered systematically may alsobe used in those cases where the means of administration results only ina local effect, rather than systemic.

The dose of local anesthetic will depend on the anesthetic beingadministered as well as the site where the local anesthetic isadministered. For example, in embodiments where the local anesthetic isadministered via a regional block (e.g., an ankle block), the dose ofanesthetic ranges from about 1 ml up to about 30 ml of a 0.5% solution(e.g., bupivacaine). In other embodiments a 3 mg/kg dose (maximum 200mg) of a 2% solution (e.g., lidocaine) can be administered byintra-articular infiltration. In other embodiments the dose of localanesthetic can range between 0.5 ml to about 60 ml of a 0.25% to 5%solution.

Alternatively, phenol can be administered at the surgical site or openwound to be treated in place of (or in addition to) a local anestheticto anesthesize the area. Phenol can preferably be administered prior toadministration of the capsaicinoid, or can be co-administered with thedose of capsaicinoid. By co-administration it is meant either theadministration of a single composition containing both the capsaicinoidand the phenol, or the administration of the capsaicinoid and the phenolas separate compositions within short enough time periods that theeffective result is equivalent to that obtained when both compounds areadministered as a single composition.

Prior to the present invention, for example, in U.S. Pat. No. 4,313,958(LaHann), capsaicin is described as producing analgesia whenadministered via “systemic administration” (i.e., intrathecal, epidural,intramuscular, intravenous, intraperitoneal and subcutaneous). Animaltesting was accomplished via “stair-step dosing” which purportedly wassaid to reduce or eliminate some of the side affects of capsaicin. It isreported therein that capsaicin, when systemically delivered in finaldoses of 25 mg/kg or less prior to ultra violet radiation, preventedradiation induced hyperalgesia, but did not elevate the pain thresholdabove normal range. Only when larger doses of capsaicin wereadministered systemically, i.e. final doses of capsaicin being 50 mg/kgor greater, was the pain threshold elevated. LaHann hypothesized (butdid not exemplify), that for clinical use in humans, total doses from0.05 mg/kg to 1,000 mg/kg were acceptable and total doses from 0.25mg/kg to 500 mg/kg were preferred. The rats weighed between 125 and 175grams and the total administered dose of capsaicin ranged from 27 mg/kgto 102 mg/kg (or a total dose injected subcutaneously of about 3.375 mgto about 17.85 mg capsaicin).

More recently, U.S. Pat. No. 5,962,532 (Campbell et al) describes aninjection volume of 0.1 to 20 ml and a concentration of capsaicinbetween 0.01 to 10% for parenteral administration, which calculates to atotal dose of capsaicin of between 0.01 mg to 2,000 mg, based on volumeand concentration.

In contrast, in the present invention, the administration of microgramquantities of capsaicin into discrete localized areas, surgical sites oropen wounds responsible for the treatment and/or attenuation of painrecognizes significant advantages over system-wide exposure to milligramquantities in order to produce a therapeutic effect through alterationof sensory nerve function in a limited area.

In the present invention, a single dose from about 1 μg to 5,000 μg ofcapsaicin, or a therapeutically equivalent dose of one or more othercapsaicinoids, is administered via injection or implantation to producea selective, highly-localized destruction or incapacitation of C-fiberand/or A-delta-fiber in discrete localized areas responsible for theinitiation of pain for the purpose of eliminating pain arising from thatlocus, while minimizing potential adverse consequences of C-fiber and/orA-delta-fiber activation and/or damage outside of the locus of pain. Incertain preferred embodiments, from about 10 to about 3000 micrograms ofcapsaicin, or a therapeutically equivalent dose of one or more othercapsaicinoids, is administered at the site. In certain preferredembodiments, the amount of capsaicin administered at the site ispreferably from about 100 to about 1000 micrograms. In certain otherembodiments the amount of capsaicin administered at the site ispreferably from about 10 to about 1000 micrograms, more preferably from20 to about 300 micrograms, and most preferably from about 35 to about200 micrograms. In other words, the present invention is directed toadministration of a single dose of capsaicin or other capsaicinoid(s) byinjection or implantation in an amount that is greatly reduced ascompared to the dosage range previously considered useful by thoseskilled in the art to denervate the nerve fibers in a discrete,localized area without eliciting a systemic effect (e.g., an effectbeyond that discrete, localized location).

In other embodiments of the present invention, a single dose of fromabout 1 μg to 15,000 μg of capsaicin, or a therapeutically equivalentdose of one or more other capsaicinoids, is administered viainfiltration to produce a selective, highly-localized destruction orincapacitation of C-fiber and/or A-delta-fiber in discrete localizedareas responsible for the initiation of pain for the purpose ofeliminating pain arising from that locus, while minimizing potentialadverse consequences of C-fiber and/or A-delta-fiber activation and/ordamage outside of the locus of pain. In certain preferred embodiments,from about 600 to about 15,000 micrograms of capsaicin, or atherapeutically equivalent dose of one or more other capsaicinoids, isadministered at the surgical site or open wound. In certain preferredembodiments, the amount of capsaicin and/or preferably the range ofcapsaicin administered at the surgical site or open wound is from about1,000 to about 10,000 micrograms. In other words, the present inventionis directed to administration of a single dose of capsaicin or othercapsaicinoid(s) by infiltration in an amount that is greatly reduced ascompared to the dosage range previously considered useful by thoseskilled in the art to denervate the nerve fibers in a discrete,localized area without eliciting a systemic effect (e.g., an effectbeyond that discrete, localized location).

Capsaicinoids (capsaicin analogues) with similar physiologicalproperties, i.e., triggering C fiber membrane depolarization by openingof cation channels permeable to calcium and sodium, are known. Forexample, resiniferatoxin is described as a capsaicin analogue in U.S.Pat. No. 5,290,816 to Blumberg. U.S. Pat. No. 4,812,446 to Brand(Procter & Gamble Co.) describes other capsaicin analogues and methodsfor their preparation. U.S. Pat. No. 4,424,205 cites capsaicinanalogues. Ton et al., Brit. J. Pharm. 10:175-182 (1955) discusses thepharmacological actions of capsaicin and its analogues. Capsaicin,capsaicin analogues and other capsaicinoids are also described in detailin WO 96/40079, the disclosure of which is hereby incorporated byreference. Capsaicinoids are also described in EP0 149 545, thedisclosure of which is also hereby incorporated by reference.

Alternatively, capsaicinoids (analogues) may be administered at the sitein replacement of, part of, or all of the dose of capsaicin, thecapsaicin analogue being administered in a therapeutically equivalentamount of capsaicin for which it is substituted. Where a capsaicinanalogue is selected to replace some or all of the capsaicin, thecapsaicin analogue can be selected from those compounds with similarphysiological properties to capsaicin as are known in the art.Resiniferatoxin qualitatively resembles capsaicin in its activity, butdiffers quantitatively in potency (i.e. 103-104 fold more potent) and inrelative spectrum of actions. For resiniferatoxin it is recommended toadminister 0.1×10−3 to 5×10−2 mg/kg, preferably 0.1×10−3 to 5×10−3mg/kg, body weight of the subject for single application, or less uponmultiple application. In certain embodiments, resiniferatoxin isadministered in the range of 1×10−5 mg/kg to 5×10−2 mg/kg to thesubject. Resiniferatoxin also shows a somewhat different spectrum ofaction, providing greater relief of pain at a given dose. Therefore, thedose of resiniferatoxin should be at least 100 fold less than a dose ofcapsaicin alone.

Other suitable capsaicin analogues preferably include, but are notlimited to, N-vanillylnonanamides, N-vanillylsulfonamides,N-vanillylureas, N-vanillylcarbamates, N[(substitutedphenyl)methyl]alkylamides, methylene substituted N[(substitutedphenyl)methyl]alkanamides, N[(substitutedphenyl)methyl]-cis-monosaturated alkenamides, N[(substitutedphenyl)methyl]diunsaturated amides, 3-hydroxyacetanilide,hydroxyphenylacetamides, pseudocapsaicin, dihydrocapsaicin,nordihydrocapsaicin, homocapsaicin, homodihydrocapsaicin I, anandamide,piperine, zingerone, warburganal, polygodial, aframodial, cinnamodial,cinnamosmolide, cinnamolide, civamde, nonivamide, olvanil,N-oleyl-homovanillamidia, isovelleral, scalaradial, ancistrodial,β-acaridial, merulidial, scutigeral and any combinations or mixturesthereof.

In certain embodiments, the capsaicinoid utilized in the compositionsand methods of the invention is capsaicin itself. In certain preferredembodiments, the capsaicin is in a purified form obtained from thechemical purification of Capsaicin USP. In certain preferredembodiments, the purified capsaicin used in the compositions and methodsof the invention consists essentially of the trans isomer. Thetrans-isomer of capsaicin has its activity at the vanilloid receptor,and this embodiment, the methods and formulation of the presentinvention are especially useful for treating disorders or pain that canbe alleviated through activation of the vanilloid receptors via the VR-1mechanism. Whereas Capsaicin USP contains only about 55-60%trans-capsaicin, with the remainder comprising the precursorsdihydrocapsaicin and nordihydrocapsaicin, in such embodiments theformulation preferably consists essentially of trans-capsaicin, e.g.,preferably having a purity of greater than about 97%, preferably greaterthan about 98%, more preferably greater than about 99% trans-capsaicin.

The trans isomer is preferably prepared in accordance with the methodfor synthesizing the trans isomer of capsaicin from a four step processand purified as describe in U.S. Provisional Application No. 60/461,164filed Apr. 8, 2003, the disclosure of which is hereby incorporated byreference in its entirety. In accordance with U.S. ProvisionalApplication No. 60/461,164 said method for synthesizing the trans isomerof capsaicin comprises a) alkylating 3-methyl butyne with halovalericacid and/or -haloalkanic acid to obtain 8-methyl-6-nonynoic acid and/oralkynoic acid analogues thereof; b) reducing said 8-methyl-6-nonynoicacid to obtain trans-8-methyl-nonenoic acid; c) activating the8-methyl-nonenoic acid to obtain an acid chloride; and d) acylating4-hydroxy-3-methoxybenzylamine hydrochloride with the acid chloride toobtain trans-capsaicin.

In certain embodiments, step a) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)mixing anhydrous tetrahydrofuran (THF) with hexamethylphosphoramide(HMPA) and cooling the mixture to about −78° C. to about −75° C.; ii)adding to the mixture of step i) 3-methyl butyne followed by a dropwiseaddition of a base at a temperature from about −78° C. to about −65° C.to obtain a second mixture; iii) warming the second mixture up to about−30° C. and stirring for about 30 minutes; and iv) adding dropwise asolution of a halovaleric acid in anhydrous tetrahydrofuran at atemperature of about −30° C. for about 10 to about 15 minutes, thengradually warming to room temperature and stirring overnight to obtain areaction mixture.

In certain other embodiments, there is provided a method for obtaining acrude step a) intermediate product further comprising the steps of: i)adding 3M hydrochloric acid (HCl) to a reaction mixture and extractingthe reaction mixture with ethyl acetate; and ii) washing the extractedreaction mixture with brine to yield a crude product.

In certain embodiments, step b) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)dissolving said 8-methyl-6-nonynoic acid in a mixture of anhydroustetrahydrofuran and tertiary-butyl alcohol (t-BuOH) to obtain a solutionand cooling the solution to about −55° C. to about −40° C.; ii)condensing ammonia (NH3) to the solution to a temperature of about −50°C. to about −40° C.; iii) adding sodium drips piece-wise and stirringfrom about 30 minutes to about 2 hours at a temperature from about −45°C. to about −30° C., and iv) adding ammonium chloride (NH4Cl), warmingto room temperature and allowing the NH3 to evaporate overnight toobtain a reaction mixture. Step iii) of the step b) reaction may furthercomprise adding piece-wise lithium and stirring from about 30 minutes toabout 2 hours at a temperature from about −65 C to about −45 C.

In certain other embodiments crude step b) intermediate product furthercomprises the steps of: i) adding water to a reaction mixture; ii)acidifying the reaction mixture with 6N HCl to a pH of about 2 to about3; iii) extracting the reaction mixture with ethyl acetate, washing withbrine and drying over anhydrous sodium sulfate (Na2SO4); and iv)filtering and removing solvents under vacuum to obtain a crude step b)intermediate product.

In certain embodiments, step c) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)adding dropwise a thionyl halide to the 8-methyl-nonenoic acid at roomtemperature for about 15 minutes to about 30 minutes to form a solution;ii) heating the solution at about 50° C. to about 75 C for a period ofabout 1 hour; and iii) removing excess thionyl halide under vacuum atabout 4° C. to about 45 C to obtain a step c) intermediate product.

In certain embodiments, step d) of the method for preparation of thecapsaicin for use in the present invention comprises the steps of: i)mixing 4-hydroxy-3-methoxy benzylamine hydrochloride anddimethylformamide (DMF); ii) adding portion-wise at room temperature tothe mixture of step i) 5N sodium hydroxide (NaOH) and stirring for about30 minutes; iii) adding acid halide in anhydrous ether dropwise at atemperature of about 0° C. to about 10° C. for about 20 minutes to about1 hour; and, thereafter, iv) gradually warming the mixture to roomtemperature and stirring overnight. In certain embodiments step d)further comprises the steps of: i) adding water to the mixture andextracting the mixture with ethyl acetate to obtain an ethyl acetateextract; ii) washing said extract with 1N HCl and, thereafter, washingwith sodium bicarbonate (NaHCO3); iii) washing the solution with brineand drying over anhydrous sodium sulfate (Na2SO4); and iv) filtering andremoving solvents under vacuum to obtain a crude product.

In certain preferred embodiments, the method of preparing thetrans-capsaicin or capsaicin intermediate after one or more of the steps(e.g., a), b), c) and/or d)) further comprises purifying the crudeproduct by column chromatography, flash chromatography, or the like,using silica gel and eluting with a mixture of ethyl acetate/hexane toobtain a crude trans-capsaicin product.

Preferably after the capsaicin is formed via the 4 step process asdescribed above, the trans-capsaicin product is subjected topurification process comprising the steps of: i) dissolving the crudetrans-capsaicin product in a mixture of ether/hexane and heating themixture to about 40° C. to about 45° C.; ii) cooling the mixture to roomtemperature while stirring for about 2 hours; and iii) filtering themixture to provide a purified trans-capsaicin product.

Alternatively, or additionally to the purification process(es) asdescribed above, the capsaicin is subjected to a further purificationprocess also referred to as a “semi-prep purification” or“semi-preparative purification” of capsaicin. In the semi-preppurification, the capsaicin or previously purified capsaicin is purifiedvia the use of a semi-preparative HPLC (high performance liquidchromatography), which preferably provides for a trans-capsaicin producthaving a purity of greater than about 97%, preferably greater than about98%, more preferably greater than about 99% capsaicin.

In certain preferred embodiments, the active ingredient in thepreparation comprises substantially pure trans-capsaicin (e.g. having nomore than about 10% precursors or other capsaicin compounds such ascis-capsaicin). In more preferred embodiments, the preparation includesat least about 95% pure trans-capsaicin. In most preferred embodiments,the preparation includes at least about 99% pure trans-capsaicin. Whilethe cis-isomer of capsaicin has activity via a number of mechanisms,VR-1 is not considered to comprise a major effect of this agent.

In view of the collective activity of the trans-isomer of capsaicin atthe VR-1 receptor, it is contemplated that it is possible in certainembodiments of the present invention that the amount of trans-capsaicinincluded in the methods and formulations of the present invention willbe reduced in comparison to a preparation which includes a less pureform of capsaicin (e.g., capsaicin USP).

In other embodiments of the present invention, the formulations andmethods of the invention contemplate the use of a capsaicin agentconsisting essentially of cis-capsaicin.

Capsaicin, in either crude extract form, Capsaicin USP, or as purifiedcapsaicin, has been comprehensively studied in a variety of tests invitro, and in several animal species in vivo. Administration of a singledose of capsaicinoid according to the methods of the present inventionminimizes and/or prevents systemic delivery of the capsaicin for thepurposes of: a) producing a selective, highly-localized destruction orincapacitation of C-fibers and/or A-delta fibers in a discrete,localized area responsible for the initiation of pain (e.g.,intra-articular joints, intrabursally) for the purpose of reducing oreliminating pain arising from a discrete locus (i.e., producingantinociception), and b) minimizing potential adverse consequences ofC-fiber and/or A-delta activation and or damage outside of the locus ofpain (i.e., damage to homeostatic mechanisms, such as cardiac reflex[e.g., Bezold-Jarisch reflex] or micturation reflex [e.g., urge to void]or to nerve fibers in the central nervous system). The analgesic effectpreferably provides pain relief for at least about 48 to about 120hours, preferably from about 10 to about 21 days, more preferably fromabout 4 to about 5 weeks, even more preferably for at least about 6 toabout 8 weeks, and most preferably for at least about 16 weeks or more.

Delivery systems can also be used to administer capsaicin and localanesthetics that produce modality-specific blockade, as reported bySchneider, et al., Anesthesiology, 74:270-281 (1991), or possessphysical-chemical attributes that make them more useful for sustainedrelease then for single injection blockade, as reported by Masters, etal., Soc. Neurosci. Abstr., 18:200 (1992), the teachings of which areincorporated herein. An example of a delivery system includesmicrospheres wherein the anesthetic is incorporated into a polymermatrix in a percent loading of 0.1% to 90% by weight, preferably 5% to75% by weight. It is possible to tailor a system to deliver a specifiedloading and subsequent maintenance dose by manipulating the percent drugincorporated in the polymer and the shape of the matrix, in addition tothe form of local anesthetic (free base versus salt) and the method ofproduction. The amount of drug released per day increasesproportionately with the percentage of drug incorporated into the matrix(for example, from 5 to 10 to 20%). Other forms of delivery systemsinclude microcapsules, slabs, beads, and pellets, which in some casescan also be formulated into a paste or suspension.

The delivery systems are most preferably formed of a syntheticbiodegradable polymer, although other materials may also be used toformulate the delivery systems, including proteins, polysaccharides, andnon-biodegradable synthetic polymers. It is most preferable that thepolymer degrade in vivo over a period of less than a year, with at least50% of the polymer degrading within six months or less. Even morepreferably, the polymer will degrade significantly within a month, withat least 50% of the polymer degrading into non-toxic residues which areremoved by the body, and 100% of the capsaicin and anesthetic beingreleased within a two week period. Polymers should also preferablydegrade by hydrolysis by surface erosion, rather than by bulk erosion,so that release is not only sustained but also linear. Polymers whichmeet this criteria include some of the polyanhydrides, poly(hydroxyacids) such as co-polymers of lactic acid and glycolic acid wherein theweight ratio of lactic acid to glycolic acid is no more than 4:1 (i.e.,80% or less lactic acid to 20% or more glycolic acid by weight), andpolyorthoesters containing a catalyst or degradation enhancing compound,for example, containing at least 1% by weight anhydride catalyst such asmaleic anhydride. Other polymers include protein polymers such asgelatin and fibrin and polysaccharides such as hyaluronic acid.Polylactic acid is not useful since it takes at least one year todegrade in vivo. The polymers should be biocompatible. Biocompatibilityis enhanced by recrystallization of either the monomers forming thepolymer and/or the polymer using standard techniques.

Other local carrier or release systems can also be used, for example,the lecithin microdroplets or liposomes of Haynes, et al.,Anesthesiology 63, 490-499 (1985), or the polymer-phospholipidmicroparticles of U.S. Pat. No. 5,188,837 to Domb.

Methods for manufacture of suitable delivery systems for administrationof capsaicin alone or together with the local anesthetic are known tothose skilled in the art. The formulations may also be designed todeliver both the anesthetic and the capsaicin, either simultaneously orsequentially.

The local anesthetic can preferably be administered by direct injection,implantation or infiltration to the site where the capsaicin orcapsaicin analogue is to be administered, for example, by administeringthe local anesthetic directly in the diseased or pain producingstructure or the injured nerve or the nerve that provides innervation tothe painful area, or to effect a regional block of the area includingthe site where the capsaicin is to be administered.

In another embodiment, the local anesthetic can preferably beadministered by injection or implantation of the anesthetic into theepidural space adjacent to the spine for pain originating below apatient's waist, or directly into a joint for pain originating above thepatient's waist. The prior administration of a proximal neural blocksufficiently desensitizes C fibers to the expected pungent side effectsof the subsequent capsaicin administration.

In the embodiment wherein the anesthetic is administered asmicrospheres, the microspheres may be injected, implanted or infiltratedthrough a trochar, or the pellets or slabs may be surgically placedadjacent to nerves, prior to surgery or following repair or washing of awound. The microspheres can be administered alone when they include boththe capsaicin and local anesthetic or in combination with a solutionincluding capsaicin in an amount effective to prolong nerve blockade bythe anesthetic released from the microspheres. The suspensions, pastes,beads, and microparticles will typically include a pharmaceuticallyacceptable liquid carrier for administration to a patient, for example,sterile saline, sterile water, phosphate buffered saline, or othercommon carriers.

The expected side effects of the dose of capsaicin are believed to befrom the intense nociceptor discharge occurring during the excitatoryphase before nociceptor desensitization. However, the prioradministration of an anesthetic, such as a nerve block, proximally ordirectly to the site of administration, eliminates or substantiallyreduces such side effects. If some “breakthrough pain” occurs despitethe anesthetic, this pain may be treated by administering an analgesicsuch as a nonsteroidal anti-inflammatory agent or narcotic analgesic(i.e., the various alkaloids of opium, such as morphine, morphine salts,and morphine analogues such as normorphine). The administration of thecapsaicin can be repeated if necessary.

The administration of the anesthetic along with the subsequentadministration of capsaicin or capsaicin-like compounds alleviates painat the site for a prolonged period of time. Patients can be monitoredfor pain relief and increased movement, in the situation where treatmentis in a joint. The treatment can be repeated as necessary to control thesymptoms.

The compositions and methods of the present invention can be used fortreating various conditions associated with pain by providing painrelief at a specific site, a surgical site or open wound. Examples ofconditions to be treated include, but are not limited to, nociceptivepain (pain transmitted across intact neuronal pathways), neuropathicpain (pain caused by damage to neural structures), pain from nerveinjury (neuromas and neuromas in continuity), pain from neuralgia (painoriginating from disease and/or inflammation of nerves), pain frommyalgias (pain originating from disease and/or inflammation of muscle),pain associated with painful trigger points, pain from tumors in softtissues, pain associated with neurotransmitter-dysregulation syndromes(disruptions in quantity/quality of neurotransmitter moleculesassociated with signal transmission in normal nerves) and painassociated with orthopedic disorders such as conditions of the foot,knee, hip, spine, shoulders, elbow, hand, head and neck that requiresurgery.

The receptors involved in pain detection are aptly enough referred to asnociceptor-receptors for noxious stimuli. These nociceptors are freenerve endings that terminate just below the skin as to detect cutaneouspain. Nociceptors are also located in tendons and joints, for detectionof somatic pain and in body organs to detect visceral pain. Painreceptors are very numerous in the skin, hence pain detection here iswell defined and the source of pain can be easily localized. In tendons,joints, and body organs the pain receptors are fewer. The source of paintherefore is not readily localized. Apparently, the number ofnociceptors also influences the duration of the pain felt. Cutaneouspain typically is of short duration, but may be reactivated upon newimpacts, while somatic and visceral pain is of longer duration. It isimportant to note that almost all body tissue is equipped withnociceptors. As explained above, this is an important fact, as pain hasprimary warning functions. If we did not feel pain and if pain did notimpinge on our well-being, we would not seek help when our body aches.Nociceptive pain preferably includes, but is not limited topost-operative pain, cluster headaches, dental pain, surgical pain, painresulting from severe burns, postpartum pain, angina, genitor-urinarytract pain, pain associated with sports injuries (tendonitis, bursitis,etc. . . . ) and pain associated with joint degeneration and cystitis.

Neuropathic pain generally involves abnormalities in the nerve itself,such as degeneration of the axon or sheath. For example, in certainneuropathies the cells of the myelin sheath and/or Schwann cells may bedysfunctional, degenerative and may die, while the axon remainsunaffected. Alternatively, in certain neuropathies just the axon isdisturbed, and in certain neuropathies the axons and cells of the myelinsheath and/or Schwann cells are involved. Neuropathies may also bedistinguished by the process by which they occur and their location(e.g. arising in the spinal cord and extending outward or vice versa).Direct injury to the nerves as well as many systemic diseases canproduce this condition including AIDS/HIV, Herpes Zoster, syphilis,diabetes, and various autoimmune diseases. Neuropathic pain is oftendescribed as burning, or shooting type of pain, or tingling or itchingpain and may be unrelenting in its intensity and even more debilitatingthan the initial injury or the disease process that induced it.

Neuropathies treatable by the methods of the present invention include:syndromes of acute ascending motor paralysis with variable disturbanceof sensory function; syndromes of subacute sensorimotor paralysis;syndromes of acquired forms of chronic sensorimotor polyneuropathy;syndromes of determined forms of genetic chronic polyneuropathy;syndromes of recurrent or relapsing polyneuropathy; and syndromes ofmononeuropathy or multiple neuropathies (Adams and Victor, Principles ofNeurology, 4th ed., McGraw-Hill Information Services Company, p. 1036,1989). Syndromes of acute ascending motor paralysis are selected fromthe group consisting of acute idiopathic polyneuritis,Landry-Guillain-Barre Syndrome, acute immune-mediated polyneuritis,infectious mononucleosis polyneuritis, hepatitis polyneuritis; dipthericpolyneuropathy; porphyric polyneuropathy; toxic polyneuropathy (e.g.,thallium); acute axonal polyneuropathy; acute panautonomic neuropathy;vaccinogenic, serogenic, paraneoplastic, polyarteretic and lupuspolyneuropathy.

Syndromes of subacute sensorimotor paralysis are selected from the groupconsisting of deficiency states (e.g., beriberi, pellagra, vitamin B12);heavy metal/industrial solvent poisonings (e.g., arsenic, lead); drugoverdose (e.g., isoniazid, disulfuram, vincristine, taxol,chloramphenicol); uremic polyneuropathy; diabetes; sarcoidosis; ischemicneuropathy and peripheral vascular disease; AIDS; and radiation(radiotherapy). Syndromes of chronic sensorimotor are selected from thegroup consisting of carcinoma, myeloma and other malignancies;paraproteinemias; uremia; beriberi (usually subacute), diabetes,hypo/hyperthyroidism; connective tissue disease; amyloidosis; leprosyand sepsis. Genetic chronic polyneuropathies are selected from the groupconsisting of dominant mutilating sensory neuropathy (adult); recessivemutilating sensory neuropathy (childhood); congenital insensitivity topain; spinocerebellar degenerations, Riley Day Syndrome; UniversalAnesthesia Syndrome; polyneuropathies w/metabolic disorder; and mixedsensorimotor-autonomic type polyneuropathies. Recurrent/relapsingpolyneuropathy are selected from the group consisting of idiopathicpolyneuritis; porphyria; chronic inflammatory polyradiculoneuropathy;mononeuritis multiplex; beriberi/drug overdose; refsum disease andtangier disease. Mono/multiple neuropathies are selected from the groupconsisting of pressure palsies; traumatic neuropathies (e.g.,irradiation or electrical injury); serum, vaccinogenic (e.g., rabies,smallpox); herpes zoster; neoplastic infiltration; leprosy;diptheretic-wound infections; migrant sensory neuropathy; shingles andpost herpetic neuralgia.

Neurotransmitter-dysregulation pain syndromes, rather than involvingabnormal or damaged nerves, result from normal nerves having disruptionsin the quantity and/or quality of the various neurotransmitter moleculesassociated with signal transmission from one neuron to another. Morespecifically, sensory transmitters are released from the afferent nerveending of one nerve cell and received by receptors at the afferent endof another nerve cell. They are chemical messengers which transmit thesignal. There are numerous transmitters, including glutamate, serotonin,dopamine, norepinephrine, somatostatin, substance P, calcitoningene-related peptide, cholecystokinin, opiates and saponins. Alterationsin the quantity of transmitters and neuropeptide release, changes in theafferent receptor, changes of re-uptake of the transmitter and/orneuropeptides can all yield qualitative change of the neural signalingprocess. As a result, the aberrant signal transmission is interpreted bythe body as pain. A representative neurotransmitter dysregulationsyndrome that may be treated by the present invention includesfibromyalgia, which is a common condition characterized by a history ofchronic generalized pain and physical exam evidence of at least 11 of 18defined “tender point” sites in muscles and connective tissue (Wolfe etal., Arthritis Rheum 33:160-72, 1990). Commonly associated conditionsinclude irritable bowel syndrome, headache, irritable bladder syndrome(interstitial cystitis), sleep disturbance, and fatigue (Goldenberg,Current Opinion in Rheumatology 8:113-123, 1996; Moldofsky et al.,Psychosom Med 37:341-51, 1975; Wolfe et al., 1990; Wolfe et al., J Rheum23:3, 1996; Yunus et al., Semin Arthritis Rheum 11:151-71, 1981).

A predominant theory regarding the etiology of fibromyalgia holds thatan imbalance and/or dysregulation of neurotransmitter function may occurwithin the central nervous system (CNS), either in the brain or spinalcord and in the relation of the CNS to muscle and connective tissue viaregulatory nerve pathways (Goldenberg, 1996; Russell, Rheum Dis Clin NA15:149-167, 1989; Russell et al., J Rheumatol 19:104-9, 1992; Vaeroy etal., Pain 32:21-6, 1988; Wolfe et al., 1996). Neurotransmitters arechemical messengers, amino acids, biogenic amines and neuropeptides,emitted from nerve cells that interact with receptors on other nervecells, as well as other cell types, including muscle and immune cells.Neurotransmitter imbalance, which leads to increased pain experience,may include a qualitative and/or quantitative decrease in the functionof such neurotransmitters as glutamate, serotonin, dopamine,norepinephrine, somatostatin, substance P, calcitonin gene-relatedpeptide, cholecystokinin, opiates and saponins. Fibromyalgia ischaracterized by a relative deficit of serotonin effect and relativeexcess of substance P effect. This imbalance results in amplifiedmodulation of pain-signaling in the central nervous system, resulting inneurogenic pain (Matucci-Cerinic, Rheumatic Disease Clinics of NorthAmerica 19:975-991, 1993; Bonica, The Management of pain, Lea andFebiger, 2d ed., Philadelphia, pp. 95-121, 1990). Similar mechanisms maybe at work to cause associated conditions; for example, dysregulation ofneurotransmitter signaling in the bowel musculature, leading toirritable bowel syndrome symptoms such as cramping, diarrhea, and/orconstipation.

Neurotransmitter-dysregulation pain syndromes include, but are notlimited to the following: generalized syndromes, localized syndromes;craniofacial pain; vascular disease; rectal, perineum and externalgenitalia pain; and local syndromes of the leg/foot.

Generalized syndromes are selected from the group consisting of stumppain, causalgia, reflex sympathetic dystrophy, fibromyalgia or diffusemyofascial pain and burns. Localized syndromes are selected from thegroup consisting of trigeminal neuralgia; acute herpes zoster;panautonomic neuralgia; geniculate neuralgia (Romsay Hunt Syndrome);glossopharyngeal neuralgia; vagus nerve neuralgia and occipitalneuralgia. Craniofacial pain includes temporomandibular pain.Suboccipital and cervical musculoskeletal disorders are selected fromthe group consisting of myofascial syndrome, which includes cervicalsprain cervical hyperextension (whiplash); sternocleidomastoid muscle;trapezius muscle; and stylohyoid process syndrome (Eagle's syndrome).Vascular disease is selected from the group consisting of Raynaud'sdisease; Raynaud's phenomenon; frostbite; erythema pernio (chilblains);acrocyanosis and livedo reticularis. Rectal, perineum and externalgenitalia pain are selected from the group consisting of iliohypogastricneuralgia; iliolinguinal nerve; genotifemoral nerve and testicular pain.Local syndromes of the leg/foot are selected from the group consistingof lateral cutaneous neuropathy (neuralgia paresthetica); oobturatorneuralgia; femoral neuralgia; sciatica neuralgia; interdigital neuralgiaof the foot (Morton's metatarsalgia or neurma); injection neuropathy andpainful legs and moving toes.

Pain Intensity assessment scales are typically used by those of ordinaryskill in the art to evaluate analgesic choices and therapeutic effects.

A Visual Analogue Scale (VAS) is a measurement instrument that measuresa characteristic that is believed to range across a continuum of valuesand cannot easily be directly measured. For example, the amount of painthat a patient feels ranges across a continuum from none to an extremeamount of pain may be indirectly measured via the use of a VAS.Operationally a VAS is usually a horizontal line, 100 mm in length,anchored by word descriptors at each end, for example “no pain” at oneend and “very severe pain” at the other end. The patient, marks on theline the point that they feel represents their perception of theircurrent state. The VAS score is determined by measuring in millimetersfrom the left hand end of the line to the point that the patient marks.The 100-mm visual analog scale (VAS), a unidimensional scale that isversatile and easy to use, has been adopted in many settings.

The capsaicinoid formulations and methods described herein may be usedto treat many conditions where the capsaicinoid can be administered viainjection, implantation or infiltration into a specific site, a surgicalsite or open wound of the patient, including but not limited to thetreatment of acute or chronic pain, nociceptive and neuropathic pain,pre- and post-operative pain, cancer pain, pain associated withneurotransmitter dysregulation syndromes and orthopedic disorders,sports-related injuries, acute traumatic pain, nociceptive pain, andneurotransmitter-dysregulation syndromes.

Treatment of Chronic Post-Herniorrhaphy Pain

In a preferred embodiment, the capsaicinoid formulations and methodsdisclosed herein can be used for the treatment/attenuation of chronicpost-herniorrhaphy pain. Chronic post-herniorrhaphy pain occurs inbetween 5-30% of patients, with social consequences limiting some typeof activity in about 10% of patients and 1-4% of patients are referredto chronic pain clinics. Nerve damage is probably the most plausiblepathogenic factor, but specific principles for therapy have not beenevidence-based and range from usual analgesics to re-operation with meshremoval and various types of nerve sections without any demonstratedefficacy in sufficient follow-up studies with or without randomizeddata. In patients suffering from pain associated with chronicpost-herniorrhapy, the dose of capsaicinoid can be administered to thesite where the surgery was performed or to the immediate areasurrounding the incision.

Treatment of Pain Associated with Morton's Neuroma

In another preferred embodiment, the capsaicinoid formulations andmethods disclosed herein can be used for the treatment/attenuation ofpain associated with Morton's Neuroma. Morton's Neuroma is considered tobe most likely a mechanically induced degenerative neuropathy which hasa strong predilection for the third common digital nerve in middle-agedwomen. It is considered a well-defined model of neuropathic pain. Theusual medical treatment of Morton's neuroma includes local injection ofsteroids, often with lidocaine. When nonsurgical means fail to relievepatient's symptoms, surgical removal of this offending neuroma through adorsal approach can produce dramatic relief of symptoms in approximately80% of patients. However, 20% of patients experience neuroma recurrence(referred to as stump or amputation neuroma) that often causes moresevere pain that the original neuroma and is generally treatmentresistant. Administration of capsaicinoid in accordance with theinvention is useful for the treatment of the neuropathic pain associatedwith Morton's Neuroma and may reduce the re-occurrence of painassociated with stump or amputation neuroma.

Treatment of Pain Associated with Mastectomy

In a preferred embodiment, the capsaicinoid formulations and methodsdisclosed herein can be used for the treatment/attenuation of painassociated with mastectomy. Mastectomy results in significant pain andrequires substantial doses of opioids postoperatively. Analgesictechniques that provide good pain control while minimizing opioid sideeffects are thus highly desirable. The administration of capsaicinoid ina patient requiring a mastectomy may reduce the amount of opioidconsumption and postoperative pain scores associated with the procedure.In patients requiring a mastectomy, the dose of capsaicinoid can beadministered to the site where the surgery was performed or to themuscle, tissue and bones surrounding the surgical site.

Treatment of Pain Associated with Median Sternotomy

In another preferred embodiment, the capsaicinoid formulations andmethods disclosed herein can be used for the treatment/attenuation ofpain associated with median sternotomy. Median sternotomy is performedin patients undergoing cardiac, pulmonary, or mediastinal surgery forvarious indications. The procedure is performed through a verticalmidline incision over the sternum. After dividing the overlying midlinefascia and muscle the sternum is divided in its midline, from thesternal notch to the xiphoid process, using either a sternal saw or aLebsche knife. Bleeding edges in the periosteum are controlled withpoint electrocautery. Hemostasis of the marrow may be achieved usingbone wax or a Gel-foam/Thrombin mixture pressed into the marrow. Asternal retractor is then placed to spread the sternal edges apart andto maintain the surgical exposure. The dose of capsaicinoid can beadministered directly to the sternal edges, the muscle and/or tissuesurrounding the surgical site or directly to the bone (e.g., sternum).At completion of the procedure the sternal edges are reapproximated withstainless steel wire. The remaining wound is closed in fascial layers.Median sternotomy results in sternal instability and pain requiring notonly substantial doses of opioids postoperatively, but also substantialamounts of nursing and physical therapy time in order to ambulate thepatients. Analgesic techniques that provide good pain control whileminimizing opioid side effects are thus highly desirable. Theadministration of a capsaicinoid in a patient requiring a mediansternotomy may reduce the amount of opioid consumption and postoperativepain scores associated with the procedure.

Orthopedic Disorders

The capsaicinoid formulations and methods disclosed herein may beutilized to treat/attenuate pain associated with orthopedic disorders.Orthopedic disorders treatable via the use of the formulations andmethods of the invention include but are not limited to disorders of theknee, shoulders, back, hip, spine, elbows, foot, hand and otherdisorders, which involve pain at a specific site or body space.Orthopedic disorders affecting these locations include, but are notlimited to bursitis, tendonitis, osteoarthritis, and rheumatoidarthritis.

A. Bursitis

Bursitis is the inflammation of a bursa. Bursae are saclike cavities orpotential cavities that contain synovial fluid located at tissue siteswhere friction occurs (e.g., where tendons or muscles pass over bonyprominences). Bursae facilitate normal movement, minimize frictionbetween moving parts, and may communicate with joints. In the normalstate, the bursa provides a slippery surface that has almost nofriction. A problem arises when a bursa becomes inflamed. The bursaloses its gliding capabilities, and becomes more and more irritated whenit is moved. When the condition called bursitis occurs, the slipperybursa sac becomes swollen and inflamed. The added bulk of the swollenbursa causes more friction within already confined spaces. Also, thesmooth gliding bursa becomes gritty and rough. Movement of an inflamedbursa are painful and irritating. Bursitis usually occurs in theshoulder (subacromial or subdeltoid bursitis). Other sites include theolecranoh (miners' elbow), prepatellar (housemaid's knee) orsuprapatellar, retrocalcaneal (Achilles), iliopectineal (iliopsoas) ofthe hip, ischial (tailor's or weaver's bottom) of the pelvis, greatertrochanteric of the femur, and first metatarsal head (bunion). Bursitismay be caused by trauma, chronic overuse, inflammatory arthritis (eg,gout, rheumatoid arthritis), or acute or chronic infection (eg, pyogenicorganisms, particularly Staphylococcus aureus; tuberculous organisms,which now rarely cause bursitis). Orthopedic disorders of the footinclude, but are not limited to, heel spurs, corns, bunions, Morton'sneuroma, hammertoes, ankle sprain, fractures of the ankle or metatarsalsor sesamoid bone or toes, plantar fascitis and injuries to the achillestendon. Orthopedic disorders of the hand include, but are not limitedto, arthritis, carpal tunnel syndrome, ganglion cysts, tendon problemssuch as lateral epicondylitis, medial epicondylitis, rotator cufftendonitis, DeQuervian's tenosynovitis, and trigger finger/triggerthumb. Other orthopedic disorders include, but are not limited to,Paget's disease, scoliosis, soft-tissue injuries such as contusions,sprains and strains, long bone fractures and various other sportsinjuries some of which include patellar tendonitis and lumbar strain.

Treatment of non-infected acute bursitis has mainly consisted oftemporary rest or immobilization and high-dose NSAIDs, sometimesnarcotic analgesics, may be helpful. Voluntary movement should beincreased as pain subsides. Pendulum exercises are particularly helpfulfor the shoulder joint. Aspiration and intrabursal injection of depotcorticosteroids 0.5 to 1 ml (triamcinolone diacetate 25 or 40 mg/ml)mixed with at least 3 to 5 ml of local anesthetic after infiltrationwith 1% local anesthetic (e.g., lidocaine) is the treatment of choicewhen rest alone is inadequate. The depot corticosteroid dose and volumeof mixture are gauged to the size of the bursa. Respiration andinjection may be required with resistant inflammation. Systemiccorticosteroids (prednisone 15 to 30 mg/day or equivalent for 3 days)are occasionally indicated in resistant acute cases after infection andgout have been excluded. Chronic bursitis is treated as acute bursitis,except that splinting and rest are less likely to be helpful. Surgery israrely needed to treat bursitis and is usually done only in the chroniccases that have not improved with traditional therapy. The most commonsurgical treatment, if needed, is an Incision and Drainage (called an Iand D) and is used only in cases of infected bursa. The surgeon firstnumbs the skin with an anesthetic and then opens the bursa with ascalpel. Finally, the surgeon drains the fluid present in the inflamedbursa. Sometimes it is necessary to excise the entire bursa surgically.This is indicated only if the bursal swelling causes problems.

The capsaicinoid may be administered via injection in a location andfashion similar to that currently utilized with respect to localizedinjections of corticosteroids. For example, in certain embodiments, thedose of capsaicin is administered by intra-articular injection into thebursa.

In another embodiments, the capsaicinoid may be administered viainfiltration into the bursa and/or the tissue and muscle surrounding thebursa.

B. Tendonitis

The capsaicinoid formulations and methods disclosed herein may beutilized to treat/attenuate pain associated with tendonitis(inflammation of the tendons) and tendonitis surgery. When tendonsbecome inflamed, the action of pulling the muscle becomes irritating andpainful. The cause is often unknown. Most instances tendonitis occurs inmiddle-aged or older persons as the vascularity of tendons attenuates;repetitive microtrauma may increase injury. Repeated or extreme trauma(short of rupture), strain, or excessive (unaccustomed) exercise is mostfrequently implicated. The most common cause of tendonitis is overuse.Commonly, individuals begin an exercise program, or increase their levelof exercise, and begin to experience symptoms of tendonitis. The tendonis unaccustomed to the new level of demand, and this overuse will causean inflammation and tendonitis. Tendonitis produces pain, tenderness andstiffness near a joint which is aggravated by movement.

General practitioners commonly use non-steroidal anti-inflammatory drugsNSAIDs) to treat tennis elbow, but there are no trials to date that havecompared them with other painkillers and one study found no clinicallyimportant benefit over placebo. Symptomatic relief is provided by restor immobilization (splint or cast) of the tendon, application of heatfor chronic inflammation or cold for acute inflammation (whicheverbenefits the patient should be used), local analgesic drugs, and NSAIDsfor 7 to 10 days. A critical review of the role of variousanti-inflammatory medications in tendon disorders found limited evidenceof short-term pain relief and no evidence of their effectiveness inproviding even medium term clinical resolution. Use of corticosteroidinjections provides mixed results in relief of pain and at timesinsufficient evidence to support their use. Injection of the tendonsheath with a depot corticosteroid (eg, dexamethasone acetate,methylprednisolone acetate, hydrocortisone acetate) 0.5 to 1 mL mixedwith an equal or double volume of 1% local anesthetic (eg, lidocaine)has been utilized as a treatment, depending on severity and site. Theinjection is made blindly or proximal to the site of maximum tendernessif the specific inflammation site cannot be identified. Particular careshould be taken not to inject the tendon per se (which offers greaterresistance) because it may be weakened and rupture in active persons.Reexamination of a less inflamed site 3 or 4 days later often disclosesthe specific lesion, and a second injection can be made with greaterprecision. Rest of the injected part is advisable to diminish risk oftendon rupture. Although complications associated with intrarticular andsoft tissue steroid injection are relatively uncommon, when acomplication does occur, it can result in severe and disablingconsequences for the subject. A small proportion of subjects fail torespond to only one injection of corticosteroid and some subjects whoinitially improve at four weeks had worst symptoms by six months.Therefore with this lack of consensus, no good evidence to support theuse of local corticosteroid injections and the unknown long-termside-effects of using steroids, an alternative treatment must be sought.Surgery is rarely necessary, except for release of fibro-osseous tunnels(as in de Quervain's disease) or for tenosynovectomy of chronicinflammation (as in rheumatoid arthritis).

In one embodiment of the present invention, pain associated withtendonitis of the knee, shoulders, hip, pelvis, spine, elbows, leg andfoot is treated with a capsaicinoid injection undertaken in similarfashion as a localized corticosteroid injection. For example, inembodiments where the capsaicinoid formulation is used for thetreatment/attenuation of pain associated with tendonitis or bursitis ofthe shoulder, the dose of capsaicinoid can be administered by injectioninto the subacromial bursa with the needle inserted into the spacebetween the acromium and the humerus on the lateral aspect of theshoulder.

In another embodiment of the present invention, when surgery for thetreatment of tendonitis is required, pain associated with tendonitis andtendonitis surgery of the knee, shoulders, hip, pelvis, spine, elbows,leg and foot is treated with administration via infiltration of acapsaicinoid directly into the affected tendon. In other embodiments,and in addition to administration to the affected tendon, the capsaicincan be administered by infiltration to the muscle and tissue surroundingthe affected tendon.

C. Osteoarthritis

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with osteoarthritis (degenerativejoint disease) and osteoarthritis surgery. Osteoarthritis ischaracterized by the breakdown of the joint's cartilage. Cartilage isthe part of the joint that cushions the ends of bones. Cartilagebreakdown causes bones to rub against each other, causing pain and lossof movement. Most commonly affecting middle-aged and older people,osteoarthritis can range from very mild to very severe. It affects handsand weight-bearing joints such as knees, hips, feet and the back. Thereare many factors that can cause osteoarthritis, including but notlimited to age, genetics, obesity, sports-related activities,work-related activities, or accidents. Treatment of osteoarthritisfocuses on decreasing pain and improving joint movement, and mayinclude: Exercises to keep joints flexible and improve muscle strength;Many different medications are used to control pain, includingcorticosteroids and NSAIDs, glucocorticoids injected into joints thatare inflamed and not responsive to NSAIDS. For mild pain withoutinflammation, acetaminophen may be used; heat/cold therapy for temporarypain relief; joint protection to prevent strain or stress on painfuljoints; surgery (sometimes) to relieve chronic pain in damaged joints;and weight control to prevent extra stress on weight-bearing joints.

Surgical treatment to replace or repair damaged joints is indicated insevere, debilitating disease. Surgical options include: arthroplasty(total or partial replacement of the deteriorated joint with anartificial joint; arthroscopic surgery to trim torn and damagedcartilage and wash out the joint; osteotomy (change in the alignment ofa bone to relieve stress on the bone or joint); and arthrodesis(surgical fusion of bones, usually in the spine).

Pain associated with osteoarthritis and osteoarthritis surgery may betreated/attenuated with the capsaicinoid formulations administered viainfiltration into the affected joint, e.g., by intra-articular injectionat the affected site or by intra-articular infiltration and/or to thetissue and muscle surrounding the affected joint, including but notlimited to osteoarthritis disorders of the knee

D. Rheumatoid Arthritis

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with rheumatoid arthritis and surgeryto treat or attenuate rheumatoid arthritis. Rheumatoid arthritis is achronic, systemic, inflammatory disease that chiefly affects thesynovial membranes of multiple joints in the body. Because the diseaseis systemic, there are many extra-articular features of the disease aswell. Rheumatoid Arthritis can affect many joints in the body, includingthe knee, ankle, elbow, and wrist. Joints that are actively involvedwith the disease are usually tender, swollen, and likely demonstratereduced motion. The disease is considered an autoimmune disease that isacquired and in which genetic factors appear to play a role.

In patients with progressive rheumatoid arthritis, joint pathology mayoccur despite appropriate conservative measures. In such patients, lossof joint function usually causes a loss of functional ability.Therefore, surgery is usually performed on joints that have caused thepatient a significant loss of function. Surgery is not without riskshowever, and therefore the decision to operate must be carefully made.Synovectomy is done to remove diseased portions of the joint synovium.Ideally, this type of surgery is performed before there is destructionof cartilage. Total joint arthroplasty is performed when there issignificant destruction of the bones forming the joint resulting in lossof function, or there is significant pain in the joint limitingfunction. “Total” means that the ends of both bones that comprise thejoint have diseased portions that are surgically removed and replacedwith man-made components (i.e., a prosthesis). The hip and knee arecommon sites for total joint arthroplasty in the patient with rheumatoidarthritis and therefore are the sites of many complications of thesurgery. Complications include: infections, dislocation, loosening ofthe prosthetic components from the bone, breakage of the prostheticcomponents, and fractures of bones caused by the prosthetic devices,usually the result of a loss of bone density. In some cases where thetotal joint replacement fails, the prosthetic components are removedfrom the bone. In the case of the hip joint, this procedure (GirdlestoneExcision) leaves the femur without the anatomical neck or head resultingin a soft tissue “joint” between the femur and pelvis. In some patients,the shoulder becomes very painful and/or mechanically non-functional.Total shoulder arthroplasty may be indicated in these patients. There isevidence that a majority patients that have had total shoulderarthroplasty secondary to significant pain have obtained substantialpain relief.

There are several different classes of drugs utilized to treat patientswith the various types of rheumatic disease. These classes includeanalgesics to control pain, corticosteroids, uric acid-lowering drugs,immunosuppressive drugs, nonsteroidal anti-inflammatory drugs, anddisease-modifying antirheumatic drugs.

Pain associated with rheumatoid arthritis and rheumatoid arthritissurgery may be treated/attenuated with the capsaicinoid formulationsadministered via infiltration into the affected joint. In otherembodiments, and in addition to administration to the affected joint,the capsaicinoid can be administered by infiltration to the muscle andtissue surrounding the affected joint.

E. Back Pain

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with back pain. Back pain is thesecond most common reason for doctor visits in the U.S. The causes oflower back pain are numerous. Some of the more common causes of lowerback pain are: sudden injury to the back such as may occur in an autoaccident, fall, sports, or other manner; gynecological conditions suchas endometriosis, menstrual cramps, fibroid tumors, and pregnancy aresometimes the cause of lower back pain in women; and stress to themuscles, nerves, or ligaments in the lower back. Slipped discs, pinchednerves, sciatica, aging, and infections are other common causes of lowerback pain. The treatment of lumbar strain consists of resting the back(to avoid re-injury), medications to relieve pain and muscle spasm,local heat applications, massage, and eventual (after the acute episoderesolves) reconditioning exercises to strengthen the low back andabdominal muscles Zygapophysial joints, better known as facet or “Z”joints, are located on the back (posterior) of the spine on each side ofthe vertebrae where it overlaps the neighboring vertebrae. The facetjoints provide stability and give the spine the ability to bend andtwist. They are made up of the two surfaces of the adjacent vertebrae,which are separated by a thin layer of cartilage. The joint issurrounded by a sac-like capsule and is filled with synovial fluid (alubricating liquid that reduces the friction between the two bonesurfaces when the spine moves and also nourishes the cartilage.) Aproblem (such as inflammation, irritation, swelling or arthritis) in thefacet joint may cause low back pain. Diagnostic tests can show anabnormality in a facet joint, which may suggest that the facet joint isthe source of the pain. However, sometimes normal study results can bepresent while the facet joint is still the source of pain, and abnormalresults do not always implicate the facet joint.

To determine if a facet joint is truly the source of back pain, aninjection of local anesthetic (e.g, as a block) may be utilized. If aninjection of a small amount of anesthetic or numbing medication into thefacet joint reduces or removes the pain, it indicates that the facetjoint may be the source of the pain. This is diagnostic use of the facetjoint injection. Once a facet joint is pinpointed as a source of pain,therapeutic injections of anesthetic agents and anti-inflammatorymedications may give pain relief for longer periods of time. Thecapsaicinoid formulations may be administered in such situations toattenuate such pain.

Facet joint injections are performed while the patient is awake, under alocal anesthetic, and able to communicate. Sometimes, the health careprovider may also administer drugs to make the patient more comfortableduring the procedure. The injection is usually performed while thepatient is lying on his or her stomach on an X-ray table. EKG, bloodpressure cuffs and blood-oxygen monitoring devices may be hooked upprior to the injection process. Once the proper site has beendetermined, the physician will inject the anesthetic (often lidocaine orbupivicaine) and the anti-inflammatory (usually a corticosteroid.). Thisprocess may then be repeated depending on the number of affected facetjoints.

F. Heel Spur

The capsaicinoid formulations and methods disclosed herein may be usedto treat/attenuate pain associated with a heel spur, which is aprojection or growth of bone where certain muscles and soft tissuestructures of the foot attach to the bottom of the heel, or heel spursurgery. Most commonly, the plantar fascia, a broad, ligament-likestructure extending from the heel bone to the base of the toes becomesinflamed, and symptoms of heel pain begin. As this inflammationcontinues over a period of time, with or without treatment, a heel spuris likely to form. If heel pain is treated early, conservative therapyis often successful and surgery is usually avoided. Early signs of heelpain are usually due to plantar fasciitis, the inflammation of theplantar fascia. It is probably the most common cause of heel pain seenby the podiatrist. It is seen in all groups of people; runners,athletes, week-end warriors, people who have jobs requiring a fairamount of standing, walking, or lifting, and those who have recentlygained weight. Initially, patients receive taping of the foot and whenindicated, cortisone injections or a short course an anti-inflammatorymedication, taken orally. Exercises, night splints, and physical therapyare used as adjunct methods to try to reduce the inflammation. Ifsuccessful, a custom made in shoe orthotic is made to control theabnormal stress and strain on the plantar fascia resulting in remissionof the majority of the symptoms. In some instances, conservative therapyfails, and surgery is indicated. Many times an endoscopic procedure,called a plantar fasciotomy, is done in which a release of some of thefibers of the plantar fascia is performed through two, small incisionson each side of the heel. Recovery is often 2 weeks or less, with thepatient walking with only a surgical shoe 24 hours after surgery. Whenthe plantar fascia undergoes mico-herniations (tears), a heel spur maydevelop. Again, if treated early, even patients with spurs findsatisfactory remission of symptoms with conservative therapy such aspadding, strapping, injections and in-shoe orthotics. Unfortunatelythere are those whose symptoms are severe enough to prevent them fromperforming their job or recreational activities, and surgery is thenindicated. Surgery involves releasing a part of the plantar fascia fromits insertion in the heel bone, as well as removing the spur. Many timesduring the procedure, pinched nerves (neuromas), adding to the pain, arefound and removed. Often, an inflamed sac of fluid call a accessory oradventitious bursa is found under the heel spur, and it is removed aswell. Post operative recovery is usually a slipper cast and minimalweight bearing for a period of 2-3 weeks. On some occasions, a removableshort-leg walking boot is used or a below knee cast applied. After theyare removed normal weight-bearing is allowed and the patient us treatedwith in-office physical therapy.

When a capsaicinoid is used for plantar fascia, the dose of capsaicinoidis preferably administered by injection into the affected area. Whensurgery is required, the dose of capsaicinoid is preferably administeredby infiltration into the heel bone after the surgical incision is madeand/or to the tissue and muscle surrounding the heel bone.

Treatment of Pain Associated with Laparoscopic Cholecystectomy

In another preferred embodiment, the capsaicinoid formulations andmethods disclosed herein can be used for the treatment/attenuation ofpain associated with laparoscopic cholecystectomy. Laparoscopiccholecystectomies have virtually replaced open surgical cholecystectomy.However, patients undergoing laparoscopic cholecystectomies still havepain. Pain control following surgery typically includes use of opioids,especially within the first several days after surgery. Theadministration of a capsaicinoid in a patient who has undergone alaparoscopic cholecystectomy may reduce the amount of opioid consumptionand postoperative pain scores associated with the procedure. In patientsrequiring a laparoscopic cholecystectomy, the dose of capsaicinoid canbe administered either by injection, infiltration or both injection andinfiltration. When the dose of capsaicinoid is administered byinjection, the capsaicinoid may be injected directly the site ofincision or to the immediate area surrounding the surgical site. Inother embodiments, the dose of capsaicinoid can be administered to thesite where the surgery is being performed or to the muscle, tissue andbones surrounding the surgical site prior to closure of the wound. Incertain other embodiments, the capsaicinoid formulations and methodsdisclosed herein can be used for the treatment/attenuation of painassociated with cholecystectomy requiring a more invasive surgery than alaparoscopy.

Infiltration Dose

In preferred embodiments of the present invention, the dose ofcapsaicinoid contained in a unit dose for infiltration is from about 1μg to about 15,000 μg of capsaicin, preferably from about 600 μg toabout 15,000 μg capsaicin, more preferably from about 600 μg to about10,000 μg capsaicin, or a therapeutically equivalent amount of one ormore capsaicinoids. In certain preferred embodiments, the dose ofcapsaicin is from about 1000 μg to about 10,000 μg, or a therapeuticallyequivalent amount of one or more capsaicinoids. Preferably, thecapsaicinoid is administered in a pharmaceutically and physiologicallyacceptable vehicle for injection or implantation.

In certain other embodiments, suitable doses of capsaicin/capsaicinoidfor infiltration for the treatment of nociceptive pain, neuropathicpain, pain from nerve injury, pain from myalgias, pain associated withpainful trigger points, pain from tumors in soft tissues, painassociated with neurotransmitter-dysregulation syndromes and painassociated with orthopedic disorders range from about 600 μg to about15,000 μg of capsaicin (trans 8-methyl-N-vanillyl-6-noneamide),preferably from about 600 to about 10,000 micrograms, more preferablyfrom about 1000 to 10,000 micrograms, with 5,000 μg most preferred.

In certain preferred embodiments, an injection of local anesthetic canbe administered in proximity to the site prior to administration of thecapsaicinoid, e.g., as described above and in the appended examples. Inother embodiments, phenol can be used instead of or in addition to thelocal anesthetic.

Injectable Dose

In preferred embodiments of the present invention, the dose ofcapsaicinoid contained in a unit dose injection/implantation is fromabout 1 μg to about 5000 μg of capsaicin, preferably from about 10 μg toabout 3000 μg capsaicin, more preferably from about 300 μg to about 1500μg capsaicin, or a therapeutically equivalent amount of one or morecapsaicinoids. In certain preferred embodiments, the dose of capsaicinis from about 400 μg to about 1200 μg, or a therapeutically equivalentamount of one or more capsaicinoids. Preferably, the capsaicinoid isadministered in a pharmaceutically and physiologically acceptablevehicle for injection or implantation.

In certain other embodiments, suitable doses of capsaicin/capsaicinoidfor injection or implantation for the treatment of nociceptive pain,neuropathic pain, pain from nerve injury, pain from myalgias, painassociated with painful trigger points, pain from tumors in softtissues, pain associated with neurotransmitter-dysregulation syndromesand pain associated with orthopedic disorders range from about 1 μg toabout 3000 μg of capsaicin (trans 8-methyl-N-vanillyl-6-noneamide),preferably from about 20 to about 300 micrograms, more preferably fromabout 35 to 200 micrograms, with 100 μg most preferred.

The administration of the anesthetic along with the subsequentadministration of the capsaicinoid formulations and methods of theinvention alleviate or attenuate pain at the site for a prolonged periodof time. With respect to joint pain, in certain preferred embodiments asingle unit dose capsaicinoid injection or implantation attenuates painat the site for at least about one month, more preferably at least about3 months, and typically in certain embodiments from about 3 to about 6months. With respect to pain associated with arthritic conditions suchas osteoarthritis, in certain preferred embodiments a single unit dosecapsaicinoid injection or implantation attenuates pain at the site forat least about 3 months to at least about 4 months. With respect topost-surgical pain, in certain preferred embodiments a single unit dosecapsaicinoid injection or implantation attenuates pain at the site forat least about one week, and in certain embodiments for at least about 1month. Patients can be monitored for pain relief and increased movement,in the situation where treatment is in a joint. The treatment can berepeated as necessary to control the symptoms.

In certain preferred embodiments, an injection of local anesthetic canbe administered in proximity to the site prior to administration of thecapsaicinoid, e.g., as described above and in the appended examples. Inother embodiments, phenol can be used instead of or in addition to thelocal anesthetic.

Injectable/Implantable and Infiltratable Formulations

In embodiments where the capsaicinoid is administered by injection,implantation or infiltration, the capsaicinoid is administered to adiscrete site by penetrating the outer layer of the skin or a surgicalsite or wound opening by instillation or injection to the site or woundopening (e.g., tissue, muscle, and bone) with an instrument known tothose skilled in the art for administering agents via infiltration,e.g., a needle and syringe.

The dose of capsaicinoid is preferably prepared for injection,implantation or infiltration by being incorporated into apharmaceutically and physiologically acceptable vehicle foradministration into a surgical site or wound opening of the patient(e.g., human or animal). For example, the capsaicinoid may be dissolvedin oils, propyleneglycol or other solvents commonly used to prepareinjectable, implantable or infiltratable solutions. Suitablepharmaceutically acceptable vehicles preferably include aqueousvehicles, nonaqueous vehicles, antimicrobial agents, isotonic agents,buffers, antioxidants, suspending and dispersing agents, emulsifyingagents, sequestering or chelating agents and any combinations ormixtures thereof. Examples of aqueous vehicles preferably include SodiumChloride Injection, Bacteriostatic Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Bacteriostatic Sterile Water Injection, Dextrose Lactated RingersInjection and any combinations or mixtures thereof. Nonaqueousparenteral vehicles preferably include fixed oils of vegetable origin,cottonseed oil, corn oil, sesame oil, peanut oil and any combinations ormixtures thereof. Antimicrobial agents in bacteriostatic or fungistaticconcentrations preferably include phenols, cresols, mercurials, benzylalcohol, chlorobutanol, ethyl and propyl p-hydroxybenzoic acid esters,thimerosal, benzalkonium chloride benzethonium chloride and mixturesthereof. Isotonic agents preferably include sodium chloride, dextroseand any combinations or mixtures thereof. Buffers preferably includeacetate, phosphate, citrate and any combinations or mixtures thereof.Antioxidants preferably include ascorbic acid, sodium bisulfate and anycombinations or mixtures thereof. Suspending and dispersing agentspreferably include sodium carboxymethylcelluose, hydroxypropylmethylcellulose, polyvinylpyrrolidone and any combinations or mixturesthereof. Emulsifying agents preferably include Polysorbate 80 (Tween80). Sequestering or chelating agents of metal ions preferably includeethylenediaminetetraacetic acid. Additional pharmaceutically acceptablevehicles also preferably include ethyl alcohol, polyethylene glycol,glycerin and propylene glycol for water miscible vehicles and sodiumhydroxide, hydrochloric acid, citric acid or lactic acid for pHadjustment and any combinations or mixtures thereof.

Depending on the pharmaceutically acceptable vehicle chosen, the dose ofcapsaicinoid can be administered as an aqueous solution or suspensionfor injection, implantation or infiltration. Injections or infiltrationsmay be separated into five distinct types, generally classified as (i)medicaments or solutions or emulsions suitable for infiltration; (ii)dry solids or liquid concentrates containing no buffers, diluents, orother added substances, and which upon the addition of suitablevehicles, yield solutions conforming in all aspects to the requirementsfor infiltration; (iii) preparations as described in (ii) except thatthey contain one or more buffers, diluents or other added substances;(iv) solids which are suspended in a suitable fluid medium and which arenot to be injected intravenously or into the spinal canal; and (v) drysolids, which upon the addition of suitable vehicles, yield preparationsconforming in all respects to the requirements of Sterile Suspensions(see: H. C. Ansel, Introduction to Pharmaceutical Dosage Forms, 4thEdit., 1985, pg. 238).

In certain other embodiments, a surfactant can preferably be combinedwith one or more of the pharmaceutically acceptable vehicles previouslydescribed herein so that the surfactant or buffering agent prevents theinitial stinging or burning discomfort associated with capsaicinoidadministration, as a wetting agent, emulsifier, solubilizer and/orantimicrobial.

Suitable surfactants include, but are not limited to, sodium stearylfumarate, diethanolamine cetyl sulfate, polyethylene glycol,isostearate, polyethoxylated castor oil, benzalkonium chloride, nonoxyl10, octoxynol 9, polyoxyethylene sorbitan fatty acids (polysorbate 20,40, 60 and 80), sodium lauryl sulfate, sorbitan esters (sorbitanmonolaurate, sorbitan monooleate, sorbitan monopalmitate, sorbitanmonostearate, sorbitan sesquioleate, sorbitan trioleate, sorbitantristearate, sorbitan laurate, sorbitan oleate, sorbitan palmitate,sorbitan stearate, sorbitan dioleate, sorbitan sesqui-isostearate,sorbitan sesquistearate, sorbitan tri-isostearate), lecithinpharmaceutical acceptable salts thereof and combinations thereof. Whenone or more surfactants are utilized in the formulations of theinvention, they may be combined, e.g., with a pharmaceuticallyacceptable vehicle and may be present in the final formulation, e.g., inan amount ranging from about 0.1% to about 20%, more preferably fromabout 0.5% to about 10%.

Buffering agents may also be used to provide drug stability; to controlthe therapeutic activity of the drug substance (Ansel, Howard C.,“Introduction to Pharmaceutical Dosage Forms,” 4th Ed., 1985); and/or toprevent the initial stinging or burning discomfort associated withcapsaicin administration. Suitable buffers include, but are not limitedto sodium bicarbonate, sodium citrate, citric acid, sodium phosphate,pharmaceutically acceptable salts thereof and combinations thereof. Whenone or more buffers are utilized in the formulations of the invention,they may be combined, e.g., with a pharmaceutically acceptable vehicleand may be present in the final formulation, e.g., in an amount rangingfrom about 0.1% to about 20%, more preferably from about 0.5,% to about10%.

In certain preferred embodiments, the pharmaceutical vehicle utilized todeliver the capsaicinoid comprises polyethylene glycol, histidine, andsucrose, in water for injection. In one preferred embodiment, thepharmaceutical vehicle comprises about 20% PEG 300, about 10 mMhistidine and about 5% sucrose in water for injection.

In other preferred embodiments, delivery systems can be used toadminister a unit dose of capsaicinoid. The dose of capsaicinoid canpreferably be administered as injectable, implantable or infiltratablemicroparticles (microcapsules and microspheres). The microparticles arepreferably in a size and distribution range suitable for infiltration.The diameter and shape of the microparticles can be manipulated tomodify the release characteristics. For example, larger diametermicroparticles will typically provide slower rates of release andreduced tissue penetration and smaller diameters of microparticles willproduce the opposite effects, relative to microparticles of differentmean diameter, but of the same composition. In addition, other particleshapes, such as cylindrical shapes, can also modify release rates byvirtue of the increased ratio of surface area to mass inherent to suchalternative geometrical shapes, relative to a spherical shape. Thediameter of microparticles preferably range in size from about 5 micronsto about 200 microns in diameter.

In a more preferred embodiment, the microparticles range in diameterfrom about 20 to about 120 microns. Methods for manufacture ofmicroparticles are well known in the art and include solventevaporation, phase separation and fluidized bed coating.

When the preferred methods of the present invention provide foradministration of a single dose of capsaicinoid alone, the single doseof capsaicinoid is preferably administered at at a discrete site, asurgical site or open wound in an amount effective to denervate thesurgical site or open wound without eliciting an effect outside the siteor wound. The single dose is preferably administered onto a nervedirectly at the site where pain relief is needed, directly into the painproducing structure, or onto a nerve that provides innervation to thepainful area via infiltration. Infiltration preferably includes, but isnot limited to, administration onto the tissue, muscle or bonesurrounding the surgical site or open wound. In other embodiments, thedose of capsaicinoid may be administered intra-articularly,intra-sternally, intrasynovially, intra-bursally or into body spaces.Injectable or implantable administration preferably includes, but is notlimited to subcutaneous (under the skin), intramuscular (muscle),intrathecal, epidural, intraperitoneal, caudal, intradermal orintracutaneous (into the skin), intercostals at a single nerve,intra-articular (joints) or body spaces, intrasynovial (joint fluid),intraspinal (spinal column), intra-arterial (arteries) administrationsand administration into other connective tissue compartments. As usedherein “intraspinal” means into or within the epidural space, theintrathecal space, the white or gray matter of the spinal cordaffiliated structures such as the dorsal root and dorsal root ganglia.Infiltratable administration of the formulations of the invention maybe, e.g., into a joint selected from the group consisting of knee,elbow, hip, sternoclavicular, temporomandibular, carpal, tarsal, wrist,ankle, intervertebral disk, ligamentum flavum and any other jointsubject to pain. Examples of body spaces include pleura, peritoneium,cranium, mediastinum, pericardium, and bursae or bursal. Examples ofbursae include acromial, bicipitoradial, cubitoradial, deltoid,infrapatellar, ishchiadica, and other bursa known to those skilled inthe art to be subject to pain.

When the single dose of capsaicinoid is administered via injection, theinjection volume of capsaicin will depend on the localized site ofadministration. Suitable injection volumes to be delivered preferablyrange from about 0.1 to about 20 ml, more preferably from about 0.5 toabout 10 ml and most preferably from about 1.0 to about 5 ml, dependingon the site to be treated. Alternatively, when the single dose ofcapsaicinoid is administered via infiltration, the volume ofcapsaicinoid administered will depend on the surgical site or size ofthe opened wound. Suitable infiltration volumes to be deliveredpreferably range from about 0.1 to about 1000 ml, more preferably fromabout 1 ml to about 100 ml and most preferably from about 5 ml to about30 ml, depending on the site or wound opening to be treated.

The administration of the anesthetic along with the subsequentadministration of capsaicinoid alleviates pain at the discrete site, thesurgical site or wound opening for a prolonged period of time. Patientscan be monitored for pain relief and increased movement, in thesituation where treatment is in a joint. The treatment can be repeatedas necessary to control the symptoms.

In certain embodiments of the invention, an adjunctive agent can beco-administered with the capsaicinoid. Suitable adjunctive agents foruse in the present invention include, but are not limited tonon-steroidal inflammatory agents (“NSAIDS”), non-anesthetic sodiumchannel blockers, vasoconstrictors, vasodilators and tricyclicanti-depressants.

In certain embodiments of the present invention, the capsaicinoid andthe adjunctive agent are administered together in a single composition.In other embodiments, the capsaicinoid and the adjunctive agent areadministered as separate compositions before, after or at the same timeas the capsaicinoid, by the same or different routes of administration.For example, the adjunctive agent can be administered orally, viaimplant, parenterally, sublingually, rectally, topically, or viainhalation. When administered in separate compositions, preferably theadjunctive agent formulation and the capsaicinoid formulation provideoverlapping duration of effect.

In certain embodiments, one or more adjunctive agents can beco-administered with the capsaicinoid. The multiple adjunctive agentscan be selected within the same group (e.g., two NSAIDS) or fromdifferent groups (e.g., an NSAID and a vasoconstrictor) and can beadministered by multiple routes of administration. Further a localanesthetic can be administered with the capsaicinoid, in addition to theadjunctive agent.

NSAIDs useful as adjunctive agents in the present invention includeaspirin, ibuprofen, diclofenac, naproxen, benoxaprofen, flurbiprofen,fenoprofen, flubufen, ketoprofen, indoprofen, piroprofen, carprofen,oxaprozin, pramoprofen, muroprofen, trioxaprofen, suprofen, aminoprofen,tiaprofenic acid, fluprofen, bucloxic acid, indomethacin, sulindac,tolmetin, zomepirac, tiopinac, zidometacin, acemetacin, fentiazac,clidanac, oxpinac, mefenamic acid, meclofenamic acid, flufenamic acid,niflumic acid tolfenamic acid, diflurisal, flufenisal, piroxicam,sudoxicam or isoxicam, pharmaceutically acceptable salts thereof, andmixtures thereof. Other suitable agents classified as NSAIDS include thefollowing, non-limiting, chemical classes of analgesic, antipyretic,nonsteroidal antiinflammatory drugs: salicylic acid derivatives,including aspirin, sodium salicylate, choline magnesium trisalicylate,salsalate, diflunisal, salicylsalicylic acid, sulfasalazine, andolsalazin; para-aminophennol derivatives including acetaminophen; indoleand indene acetic acids, including indomethacin, sulindac, and etodolac;heteroaryl acetic acids, including tolmetin, diclofenac, and ketorolac;anthranilic acids (fenamates), including mefenamic acid, andmeclofenamic acid; enolic acids, including oxicams (piroxicam,tenoxicam), and pyrazolidinediones (phenylbutazone, oxyphenthartazone);and alkanones, including nabumetone. For a more detailed description ofthe NSAIDs that may be included within the medicaments employed in thepresent invention, see Paul A. Insel Analgesic-Antipyretic andAntiinflammatory Agents and Drugs Employed in the treatment of Gout inGoodman & Gilman's The Pharmacological Basis of Therapeutics, 617-57(Perry B. Molinhoff and Raymond W. Ruddon, Eds., Ninth Edition, 1996),and Glen R. Hanson Analgesic, Antipyretic and Anti-Inflammatory Drugs inRemington: The Science and Practice of Pharmacy Vol II, 1196-1221 (A. R.Gennaro, Ed. 19th Ed. 1995) which are hereby incorporated by referencein their entireties.

NSAIDS exhibit inhibition of cyclooxygenases I and II, the enzymesresponsible for the biosynthesis of the prostaglandins and certainrelated autacoids. NSAIDs are known to be antipyretic, analgesic, andantiinflammatory. Specific classes of non-steroidals useful in thepresent invention are also disclosed in detail in the following U.S.patents, all incorporated by reference herein: U.S. Pat. No. 4,275,059,Flora, et al, issued Jun. 23, 1983, discloses salicylic acid, itspharmaceutically-acceptable salts, and its pharmaceutical-acceptableesters and derivatives; U.S. Pat. No. 4,264,582, Flora, et al, issuedApr. 28, 1981, discloses p-(isobutylphenyl)acetic acid compoundsincluding the parent acid (ibufenac) and its salts and esters, andderivatives thereof, U.S. Pat. No. 4,282,214, Flora, et al, issued Aug.4, 1981, discloses various phenylacetic acid derivatives, theirpharmaceutically-acceptable salts, and their pharmaceutically-acceptableester; U.S. Pat. No. 4,216,212, Flora, et al, issued Aug. 5, 1980,discloses prazolidine compounds, their pharmaceutically-acceptablesalts, and their pharmaceutically-acceptable esters; U.S. Pat. No.4,269,828, Flora, et al, issued May 26, 1981, discloses indolecompounds, their pharmaceutically-acceptable salts, and theirpharmaceutically-acceptable esters.

Aspirin is the prototypical nonsteroidal anti-inflammatory agent. Itpossesses analgesic-antipyrectc and anti-inflammatory properties and isthe standard for the comparison and evaluation of other nonsteroidalanti-inflammatory agents. Aspirin is a member of the class ofnonsteroidal anti-inflammatory agents known as “the salicylates.” Othersalicylates include, but are not limited to salicylic acid, methylsalicylate, diflunisal, salsalate, olsalazine and sulfasalazine.Administration of salicylates is generally recognized in the art for thetreatment of low intensity pain arising from integumental structuresrather than from viscera.

Another class of nonsteroidal anti-inflammatory agents is thepara-aminophenol derivatives; of which, acetaminophen (Tylenol™) andphenacetin are members. Acetaminophen and phenacetin possesanalgesic-antipyretic activity, however, they both posses weakanti-inflammatory activity. Therefore, these agents are a suitablesubstitute for the salicylates in the treatment of low intensity pain,but are generally not recommended for the treatment of anti-inflammatoryconditions.

In addition there are several other classes of nonsteroidalanti-inflammatory agents. These include, but are not limited to thepropionic acid derivatives, the fenamates, the oxicams, the indolederivatives, the pyrazolon derivatives and any combinations or mixturesthereof.

The proprionic acid derivatives include, but are not limited toibuprofen, naproxen, flurbiprofen, fenoprofen, ketoprofen, oxaprozin,carprofen, fenbufen, pirprofen, indobufen, indoprofen and tiaprofenicacid.

The fenamates include, but are not limited to meclofenamate sodium,mefenamic acid, flufenamic acid, tolfenamic acid, etofenamic acid,diclofenac, ketorolac and tolmetin.

The oxicams include, but are not limited to piroxicam, meloxicam,nabumetone, lornoxicam, cinnoxicam, sudoxicam, tenoxicam, and piroxicamprodrugs, e.g., ampiroxicam, droxicam, and pivoxicam.

The indole derivatives include, but are not limited to indomethacin,sulindac, and etodolac.

The pyrazolon derivatives include, but are not limited tophenylbutazone, oxyphenbutazone, antipyrine, amonopyrine, azapropazone,remifenzone and dipyrone.

Other nonsteroidal anti-inflammatory agents known as COX-II inhibitorsinclude flosulide, nimesulidde, rofecoxib, celecoxib valdecoxib andparecoxib.

Non-steroidal, anti-inflammatory agents (NSAIDs) exert most of theiranti-inflammatory, analgesic and antipyretic activity and inhibithormone-induced uterine contractions and certain types of cancer growththrough inhibition of prostaglandin G/H synthase, also known ascyclooxygenase.

Fatty acid cyclooxygenase (COX) was described as the source ofprostaglandins, thromboxanes, and a variety of other arachidonic acid-,and higher desaturated fatty acid-derived biologically activehydroxylated metabolites beginning in the late 1960's. BengtSammuelsson, Sune Bergstrom and their colleagues discovered thebiological activity and elucidated the structures of the products ofcyclooxygenase in the late 1960's and early 1970's and John Vanediscovered that aspirin and other NSAIDs exert their major biologicalactivities by inhibiting cyclooxygenase. COX is directly responsible forthe formation of PGG and PGH and these serve as the intermediates in thesynthesis of PGD, PGE, PGF, PGI, and TXA. By the late 1970's and early1980's, it was appreciated that many hormones and other biologicallyactive agents could regulate the cellular activity of COX. At first, itwas assumed that COX induction was the simple result of oxidativeinactivation of COX, which happens after only a few substrate turnovers.This is common among enzymes that incorporate molecular oxygen intotheir substrates—the oxygen rapidly degrades the enzyme. Such enzymesare sometimes referred to as suicide enzymes. In response to the rapid(within seconds) inactivation of cyclooxygenase, its message istranscribed, and the enzyme is rapidly induced to replace that lost dueto catalysis. It was noticed by several groups that cyclooxygenase wasinduced to a much greater degree than necessary to replace the lostenzyme. Using an oligonucleotide directed to the cloned COX-1 enzyme, asecond band was identified on Northern blots under low stringency. Thisgene was cloned and identified as a second COX enzyme, named COX-2, andwas found to be largely absent from many cells under basal conditionsbut rapidly induced by several cytokines and neurotransmitters. Theexpression of this enzyme was found to be largely responsible for thepreviously-observed excess COX activity in activated cells. The genesfor COX-1 and COX-2 are distinct, with the gene for COX-1 being 22 kband the message size 2.8 kb whereas the gene for COX-2 is 8.3 kb and themessage size 4.1 kb. Whereas the COX-1 promoter does not containrecognized transcription factor binding sites, the COX-2 promotercontains sites for NF-B, AP-2, NF-IL-6 and glucocorticoids (H. R.Herschman, Canc. Metas. Rev. 13: 256, 1994). There are some differencesin the active sites of the enzymes. Aspirin inhibits the cyclooxygenaseactivity of COX-1 but leaves intact its peroxidase activity, whereasaspirin converts COX-2 from a cyclooxygenase to a 15-lipoxygenase (E. A.Meade et al, J. Biol. Chem. 268: 6610, 1993).

It has been proposed that the COX-1 enzyme is responsible, in many cellsfor endogenous basal release of prostaglandins and is important in thephysiological functions of prostaglandins which include the maintenanceof gastrointestinal integrity and renal blood flow. Inhibition of COX-1causes a number of side effects including inhibition of plateletaggregation associated with disorders of coagulation, andgastrointestinal toxicity with the possibility of ulcerations and ofhemorrhage. It is believed that the gastrointestinal toxicity is due toa decrease in the biosynthesis of prostaglandins which arecytoprotective of the gastric mucosa. Thus a high incidence of sideeffects has historically been associated with chronic use of classiccyclooxygenase inhibitors, all of which are about equipotent for COX-1or COX-2, or which are COX-1-selective. While renal toxicity occurs, itusually becomes evident in patients who already exhibit renalinsufficiency (D. Kleinknecht, Sem. Nephrol. 15: 228, 1995). By far, themost prevalent and morbid toxicity is gastrointestinal. Even withrelatively nontoxic drugs such as piroxicam, up to 4% of patientsexperience gross bleeding and ulceration (M. J. S. Langman et al, Lancet343: 1075, 1994). In the United States, it is estimated that some 2000patients with rheumatoid arthritis and 20,000 patients withosteoarthritis die each year due to gastrointestinal side effectsrelated to the use of COX inhibitors. In the UK, about 30% of the annual4000 peptic ulcer-related deaths are attributable to COX inhibitors(Scrip 2162, p. 17). COX inhibitors cause gastrointestinal and renaltoxicity due to the inhibition of synthesis of homeostaticprostaglandins responsible for epithelial mucus production and renalblood flow, respectively.

The second form of cyclooxygenase, COX-2, is rapidly and readilyinducible by a number of agents including mitogens, endotoxins,hormones, cytokines and growth factors.

It has been proposed that COX-2 is mainly responsible for thepathological effects of prostaglandins, which arise when rapid inductionof COX-2 occurs in response to such agents as inflammatory agents,hormones, growth factors, and cytokines. A selective inhibitor of COX-2therefore would have anti-inflammatory, antipyretic and analgesicproperties similar to those of a conventional non-steroidalanti-inflammatory drug (NSAID). Additionally, a COX-2 inhibitor wouldinhibit hormone-induced uterine contractions and have potentialanti-cancer effects. A COX-2 inhibitor would have advantages over NSAIDSsuch as a diminished ability to induce some of the mechanism-based sideeffects. Moreover, it is believed that COX-2 inhibitors have a reducedpotential for gastrointestinal toxicity, a reduced potential for renalside effects, a reduced effect on bleeding times and a lessened abilityto induce asthma attacks in aspirin-sensitive asthmatic subjects.

Thus, compounds with high specificity for COX-2 over COX-1, may beuseful as alternatives to conventional NSAIDS. This is particularly thecase when NSAID use is contra-indicated, such as in patients with pepticulcers, gastritis, regional enteritis, ulcerative colitis,diverticulitis or with a recurrent history of gastrointestinal lesions;GI bleeding, coagulation disorders including anemia,hypoprothrombinemia, haemophelia or other bleeding problems; kidneydisease, and patients about to undergo surgery or taking anticoagulants.

Once it became clear that COX-1 but not COX-2 is responsible forgastrointestinal epithelial prostaglandin production and a majorcontributor to renal prostaglandin synthesis, the search for selectiveCOX-2 inhibitors became extremely active. This led very quickly to therecognition that several COX inhibitors, including rofecoxib (Vioxx),celecoxib (Celebrex), DUP-697, flosulide, meloxicam, 6-MNA, L-745337,nabumetone, nimesulide, NS-398, SC-5766, T-614, L-768277, GR-253035,JTE-522, RS-57067-000, SC-58125, SC-078, PD-138387, NS-398, flosulide,D-1367, SC-5766, PD-164387, etoricoxib, valdecoxib and parecoxib orpharmaceutically acceptable salts, enantiomers or tautomers thereof.

In certain embodiments, the amount of COX 2 selective inhibitor that isused in accordance with the present invention preferably ranges fromabout 0.001 to about 100 milligrams per day per kilogram of body weightof the subject (mg/day kg), more preferably from about 0.05 to about 50mg/day kg, even more preferably from about 1 to about 20 mg/day kg.

Administration of capsaicinoid alone or with a local anestheticsometimes times results in the patient experiencing a dull aching painat and around the site of local anesthetic administration. To prevent orreduce the occurrence of this dull aching pain, the non-steroidalantiinflammatory adjunctive agent is preferably administered prior tocapsaicinoid and local anesthetic administration. Preferably, thenon-steroidal antiinflammatory adjunctive agent is administered orally,which also helps to avoid the discomfort of the patient receivinganother injection. Alternatively, in certain embodiments, a selectiveCox-2 inhibitor can be administered peripherally by injection orinfiltration.

Suitable doses of the non-steroidal antiinflammatory adjunctive agentsvary due to the wide variations in potency among the various NSAIDs andthere respective selectivity for COX-1 or COX-2 inhibition. The dose isalso dependant on the severity of the pain which must be prevented oralleviated, the physical condition of the patient, the relative severityand importance of adverse side effects, and other factors within thejudgment of the physician. Examples of suitable doses and routes ofadministration for non-steroidal anti-inflammatory adjunctive agents arelisted in Tables IV-X below:

TABLE IV SALICYLATES and PARA-AMINOPHENOL DERIVATIVES NSAID Dose Aspirin325-650 mg orally every 4-6 hours Diflunisal 500-1000 mg/day orally in 2divided doses Salsalate 3 gm/day orally in 2-3 divided doses Olsalazine1 gm/day orally in 2 divided doses Sulfasalazine 1 gm every 6-8 hoursSalicylic Acid 10% or 60%; gel 6%, 12%, 17% or 26%; oint. 3%, 25% or 60%applied topically. Acetaminophen 325-650 mg orally every 4-6 hours; 1000mg orally every 6-8 hours

TABLE V PROPRIONIC ACID DERIVATIVES NSAID Dose Ibuprofen 400-800 mgorally every 6-8 hours Naproxen 500-1000 mg/day orally in 2 divideddoses Flurbiprofen 200-300 mg/day orally in 2, 3 or 4 divided dosesFenoprofen 300-600 mg orally every 6-8 hours or 200 mg orally every 4-6hours Ketoprofen 25-75 mg orally every 6-8 hours Oxaprozin 600-1200mg/day orally

TABLE VI FENAMATES NSAID Dose Meclofenamate 50 mg orally every 4-6 hoursMefenamic acid 250 mg orally every 4 hours Diclofnac 50 mg orally every8 hours; 150-200 mg/day orally in 2-4 divided doses or 100-125 mg/dayorally in 4-5 divided doses Tolmentin 400 mg orally every 8 hours or 600mg-1.8 gm/day orally Ketorolac 10 mg orally every 4-6 hours for 5 days30-60 mg intramuscular X1, then 15-30 intramuscularly every 6 hours formax. 5 days

TABLE VII OXICAMS NSAID Dose Piroxicam  10-20 mg/day orally Meloxicam7.5-15 mg/day orally Nabumetone   1000 mg/day orally, additional500-1000 mg orally if necessary

TABLE VIII INDOLE DERIVATIVES NSAID Dose Indomethacin  25-50 mg orallyor rectally every 8-12 hours Sulindac 150-200 mg orally every 12 hoursEtodolac 200-400 mg orally every 6-8 hours

TABLE IX PYRAZOLON DERIVATIVES NSAID Dose Phenylbutazone 100-200 mgorally every 6-8 hours

TABLE X COX-II INHIBITORS NSAID Dose Nimesulide    100 mg orally every12° Rofecoxib  12.5-25 mg/day orally Celecoxib 100-200 mg orally every12-24 hours

In certain embodiments, dosage levels of NSAIDs on the order of about0.05 mg/kg to about 75 mg/kg body weight per day are effective forenhancing the desired effects of localized capsaicinoid administrationand decreasing the undesired effects, or for minimizing diffusion ofcapsaicinoid from the site of administration so as to amplify either ofthe preceding. Dosage levels of NSAIDs on the order of about 5 mg/kg toabout 40 mg/kg body weight per day and dosage levels of NSAIDs on theorder of about 0.1 mg/kg to about 4 mg/kg body weight per day can alsobe administered.

In embodiments where the present invention contemplates the use of anon-anesthetic sodium channel blocker adjunctive agent, suitablenon-anesthetic sodium channel blocker adjunctive agents may include, butare not limited to aminopyridines, benzothialzoles,phenylbenzothialzoles, 5-amino-triazines, pyrazinoylguanidines,derivatives thereof and mixtures thereof, which include antiarrhythmicagents, anticonvulsant agents, diuretic agents, combinations thereof andmixtures thereof.

Suitable antiarrhythmic agents include, but are not limited todisopyramide, encainide, flecainide, lorcainide, mexilitine, moricizine,phenyloin, procamide, propafenone, quinidine, tocainide,pharmaceutically acceptable salts thereof and mixtures thereof.

Suitable anticonvulsant agents include, but are limited tocarbamezapine, lamotrigine, phenyloin, pharmaceutically acceptable saltsthereof and mixtures thereof.

Suitable diuretic agents include, but are not limited to amiloride,triamterene, pharmaceutically acceptable salts thereof and mixturesthereof.

In certain other embodiments of the present invention, thenon-anesthetic sodium channel blocker adjunctive agent can be selectedfrom the group consisting of phenyloin, carbamazepine, lamotrigine,zonisamide, riluzole, lifarizine, ralitoline, fluarizin, mexiletine,aprinidine, benzamil, phenamil, trimebutine, GEA-968, azure A,pancuronium, N-methylstrychnine, CNS 1237, BW1003C87, BW619C89, U54494A,PD85639, C1953, pharmaceutically acceptable salts thereof and mixturesthereof.

The sodium channel blockers may be administered to mammals, e.g. humans,orally at a dose of 0.1 to 10 mg/kg, or an equivalent amount of thepharmaceutically acceptable salt thereof, per day of the body weight ofthe mammal being treated. For carbamazepine, from about 50 to about 1500mg/day, preferably about to about 800 mg/day, more preferably about 100to about 600 mg/day, and most preferably about 100 to about 400 mg/day;can be orally administered. For lamotrigine, from about 50 to about 1200mg/day, preferably 100 to about 600 mg/day, more preferably about 100 toabout 450 mg/day, and most preferably about 100 to about 300 mg/day canbe orally administered.

Many of the above contemplated non-anesthetic sodium channel blockeradjunctive agents are described more fully in the literature, such as inGoodman and Gilman, The Pharmacological Basis of Therapeutics (9thEdition), McGraw-Hill, 1993, and Drug Facts and Comparisons, WoltersKluwer Co. (1999).

In another embodiment of the present invention, it is preferable toadminister the non-anesthetic sodium channel blocker adjunctive agentperipherally by injection.

In preferred embodiments, carbamazepine is the adjunctive agent and isadministered by injection or by infiltration.

Suitable doses of the non-anesthetic sodium channel blocker adjunctiveagents may vary due to the wide variations in potency among theparticular agents and there respective mechanism for decreasingpropagation and/or generation of action potentials. The doseadministered may also be dependant on the severity of the pain whichmust be prevented or alleviated, the physical condition of the patient,the relative severity and importance of adverse side effects, and otherfactors within the judgment of the physician. Examples of suitable dosesand routes of administration for the various non-anesthetic sodiumchannel blocker adjunctive agents are listed in Tables XI-XIII below:

TABLE XI Antiarrhythmic Sodium Channel Blocking Agents AntiarrhythmicDose Disopyramide 100-1600 mg/day orally Encainaide  25-300 mg/dayorally Flecainaide  50-400 mg/day orally Mexiletine 200-1200 mg/dayorally Moricizine  600-900 mg/day orally every 8 hours Phenytoin  50-600mg/day orally; intravenous injection 5 mg/kg/day Propafenone  150-900mg/day orally Procainamide     50 mg/kg/day intramuscularly or orallyQuinidine 200-1800 mg/day orally; 200 mg-600 mg intramuscular Tocainide400-1800 mg/day orally

TABLE XII Anticonvulsant Sodium Channel Blocking Agents AnticonvulsantDose Carbamazepine    5 mg/kg/day orally Lamotrigine  1-15 mg/kg/dayorally Phenytoin 50-600 mg/day orally; 5 mg/kg/day intravenous injection

TABLE XIII Diuretic Sodium Channel Blocking Agents Diuretic DoseAmiloride  5-30 gm/day orally or intravenously Triamterene 50-300 mg/dayorally

In embodiments where the present invention contemplates the use of avasoconstrictor adjunctive agent, vasoconstrictors suitable for use inthe present invention include, but are not limited to catecholamines,alpha-1 and alpha-2 adrenergic agonists, analogs thereof, activemetabolites thereof, and mixtures thereof. Catecholamines include, butare not limited to epinephrine, norepinephrine, and dopamine. Alpha-1adrenergic agonists include, but are not limited to methoxamine,phenylephrine, mephentermine, metaraminol, mitodrine, methysergide,ergotamine, ergotoxine, dihydroergotamine, sumatriptan, and mixturesthereof. Alpha-2 adrenergic agonists include, but are not limited toclonidine, guanfacine, guanabenz, methyldopa, ephedrine, amphetamine,methamphetamine, methylphenidate, ethylnorepinephrine ritalin, pemolineand other sympathomimetic agents including active metabolites, andmixtures thereof.

Each of the above contemplated vasoconstricting agents is described morefully in the literature, such as in Goodman and Gilman, ThePharmacological Basis of Therapeutics (9th Edition), McGraw-Hill, 1993,Pgs. 199-225. For example, the catecholamine epinephrine is a potentstimulant of both α- and β-adrenergic receptors. It is considered as oneof the most potent vasopressor drugs known. Epinephrine's chief vascularaction is exerted on the smaller arterioles and precapillary sphincters,although veins and large arteries also respond to epinephrineadministration. Administration of epinephrine via injection produces amarked decrease in cutaneous blood flow, constricting precapillaryvessels and small venules. Cutaneous vasoconstriction produces asignificant decrease in blood flow in the hands and feet. The markeddecrease in cutaneous blood flow after intravenous administration ofepinephrine contributes to epinephrine's slow absorption fromsubcutaneous tissues. However, absorption of epinephrine is more rapidafter intramuscular administration.

Compounds, formulations, and dosages of the vasoconstrictors describedin this method are known in the art. In certain embodiments, forexample, vasoconstrictive compositions may be used at art-recognizedeffective doses, such as, about 0.001 milligram per milliliter to about0.01 milligram per milliliter of epinephrine.

In certain embodiments, when epinephrine is administered with ananesthetic, preferably the epinephrine is added in an amount of 0.5 to 1ml (1:1000) per 100 ml of anesthetic solution for a vasoconstrictiveeffect. Preferably epinephrine 1; 100,000 or 1:200,000 dilution is used.

Norepinephrine, like epinephrine, is a potent agonist at α-receptors,but it is somewhat less potent than epinephrine. Dopamine, the immediatemetabolic precursor of norepinephrine and epinephrine, producesvasoconstriction at high concentrations, whereas, total peripheralresistance due to vasoconstriction is practically unchanged at low tointermediate doses due to dopamine's ability to reduce regional arterialresistance in the mesentary and kidneys while causing only minorincreases in other vascular beds.

The existence of more than one adrenergic receptor was first proposed in1948 by Ahlquist. His hypothesis was based on a study of the abilitiesof epinephrine, norepinephrine and other related agonists to regulatevarious physiological processes. As a result of his studies, the alpha(α) and beta (β) designations were established.

Alpha adrenergic receptors are present in many organs throughout thehuman body. However, vasoconstriction is not produced in all organs. Infact, adrenergic vasoconstriction is produced in veins and the followingarterioles: coronary, skin and mucosa, skeletal muscle, cerebral,pulmonary, abdominal viscera, salivary glands, and renal arterioles.Only alpha-1 receptors are found in skeletal muscle, cerebral,pulmonary, and abdominal viscera and both alpha-1 and alpha-2 receptorsare found in coronary, skin and mucosa, salivary glands, and renalarterioles.

When the vasoconstrictor adjunctive agents used in the present inventionare co-administered with the capsaicinoids and/or local anesthetic ofthe present invention, the vasoconstrictor adjunctive agent produces adecrease in cutaneous blood flow to the area surrounding the injectionsite, thus prolonging the activity of the capsaicinoid and/or localanesthetic at the injection site.

Suitable doses of vasoconstrictor adjunctive agents may vary due to thewide variations in potency among the particular catecholamines andadrenergic agonist and there respective selectivity for alpha-1 oralpha-2 adrenergic receptors. The dose administered may also bedependant on the severity of the pain which must be prevented oralleviated, the physical condition of the patient, the relative severityand importance of adverse side effects, and other factors within thejudgment of the physician. Examples of suitable doses and routes ofadministration for the various vasoconstrictor adjunctive agents arelisted in Tables XIV-XV below:

TABLE XIV ENDOGENOUS CATECHOLAMINES Catecholamine Dose Epinephrine 0.3-5mg by intravenous or subcutaneously

TABLE XV α-1 ADRENERGIC AGONISTS α-1 Agonist Dose Methoxamine 3-5 mgintravenously or 10-20 mg intamuscularly (during spinal anesthesia);DOA-1-1.5 hrs. Phenylephrine 2-5 mg/dose intramuscularly every 1-2 hoursas needed; intravenous bolus 0.1-0.5 mg/dose every 1-15 min as needed;100-180 mcg/min intravenous drip Mephentermine 30-45 mg intravenousl, 30mg doses repeated as required; 30-45 mg intramuscularly 1-20 min prioranesthesia. Metaraminol 2-10 mg intramusculary or intravnouslyDihydroergotamine 1-3 mg intramuscularly; 1-2 mg intravenous pushsumatriptan 1-6 mg subcutaneously

In embodiments where the present invention contemplates the use of atricyclic antidepressant adjunctive agent, the term tricyclicantidepressant adjunctive agent (“TCA” adjunctive agent), as usedherein, represents a tricyclic antidepressant agent which can beidentified as such by the skilled artisan. Tricyclic antidepressants areknown for their use in the treatment of depression. For example, Goodmanand Gilman's “The Pharmacological Basis of Therapeutics,” 9th edition,Macmillan Publishing Co., 1996, pp 413-423, provides well known examplesof tricyclic antidepressant agents. Specific tricyclic antidepressantagents useful in the present invention are also disclosed in detail inThe Merck Index, 12^(th) Edition, Merck & Co., Inc.

Tricyclic antidepressant agents useful in the present invention include,but are not limited to adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine-oxide, iprindole, lofepramine, maprotiline, melitracen,metapramine, nortriptyline, noxiptilin, opipramol, pizotyline,propizepine, protriptyline, quinupramine, tianeptine, trimipramine,pharmaceutically acceptable salts thereof and mixtures thereof.

Systemically administered antidepressants offer an alternate therapy inneuropathic and chronic pain states. Interactions with biogenic amines,endogenous opioids, excitatory amino acid receptors, substance P andcalcium and sodium channels have been considered in efforts to pinpointthe mechanism of systemically administered antidepressants (reviewed byEschalier A, Mestre C, Dubray C, Ardid D (1994) CNS Drugs 2: 261). Whatis clear is that antidepressants can act at both supraspinal (Spiegel,K., Kalb, R. and Pasternak, G. W., Ann. Neurol. 13 (1983) 462-465,Eschalier A, Mestre C, Dubray C, Ardid D (1994) CNS Drugs 2: 261) andspinal (Hwang, A. S. and Wilcox, G. L., Pain 28 (1987) 343-355;Iwashita, T. and Shimizu, T., Brain Research 581 (1992) 59-66; J.Eisenachand G. F. Gebhart, Anesthesiology 83 (1995) 1046-1054) sites ofaction.

This analgesic action is independent of antidepressant effects as itoccurs in non-depressed subjects and occurs independently of moodchanges in depressed subjects (Magni G (1991) Drugs 42: 730; Onghena P,Van Houdenhove B (1992) Pain 49: 205; Max M B (1994) In: Progress inPain Research and Management (Ed. Fields H L, Liebskind J C) IASP Press,Seattle, 229, McQuay H J, Tramer M, Nye B A, Carroll D, Wiffen P J,Moore R A (1996) Pain 68: 217). Agents which block the uptake of bothnoradrenaline (NA) and 5-hydroxytryptamine (5-HT) such as amitriptyline,or which block NA but not 5-HT, such as desipramine, are more effectivethan those with selectivity for 5-HT, such as fluoxetine (Max M B (1994)In: Progress in Pain Research and Management (Ed. Fields H L, LiebskindJ C) IASP Press, Seattle, 229). Pain relief is reported to be apparentwithin one week of therapy (McQuay H J, Carroll D, Glynn C J (1992)Anaesthesia 47: 646). This time course corresponds to the time requiredto attain stable plasma levels (t[frac12] 17-36 hours in humans, ZieglerV E, Biggs J T, Aardekani A B, Rosen S H (1978) J Clin Pharmacol 18:462). By contrast, the antidepressant activity of these compounds takes4-6 weeks to become apparent (Potter W Z, Rudorfer M, Manji H (1991) NewEng J Med 325: 633). These differences in profile of active drugs, timecourse, and independent expression of effects suggest that mechanismsunderlying pain relief and alleviation of depression differ.

In animal tests, both the systemic and spinal administration ofantidepressants show intrinsic efficacy in a number of nociceptive paintests, and augment analgesia produced by opioids (reviewed by EschalierA, Mestre C, Dubray C, Ardid D (1994) CNS Drugs 2: 261). However, thisprofile can be variable, and inhibitory effects on the action ofmorphine have been observed in some cases (reviewed by Eschalier et al.,supra). Methodological issues (e.g., test paradigm, intensity ofstimulus, dose, regimen of acute versus chronic administration) arereported to account for many of these differences (Kellstein D E,Malseed R T, Goldstein F J (1984) Pain 60: 275; Kellstein D E, Malseed RT, Ossipov M H, Goldstein F J (1988) Neuropharmacology 27: 1; Fialip J,Marty H, Makambila M C, CiViate M A, Eschalier A (1989) J Pharmacol ExpTher 248: 747). Systemically administered antidepressants also exhibitintrinsic actions in a number of neuropathic pain tests including nervetransaction (Seltzer Z. Tal M, Sherav Y (1989) Pain 37: 245),mononeuropathy (Ardid D, Gilbaud G (1992) Pain 49: 279) and diabeticneuropathy models (C. Courteix et al. (1994) Pain 57:153-160). One studyexamined chronic versus acute dosing regimens (Ardid D, Gilbaud G (1992)Pain 49: 279), and observed that the activity seen following chronicparadigms appeared to be accounted for by accumulating doses rather thanbeing qualitatively different.

The mechanism of action of the tricyclic antidepressant agents used inthe present invention is presumed to be due to the anticholinergicaction of the tricyclic antidepressant, whereby they block theneurotransmitter acetylcholine to prevent transmission of impulses inthe A-delta and C pain fibers, thereby resulting in pain relief.

Locally administered tricyclic, second generation, or third generationantidepressant(s) produce a local antinociceptive action, especiallyagainst inflammatory and neuropathic pain. When administered locally inanimal models of inflammatory (formalin test) and neuropathic pain(spinal nerve ligation), amitriptyline, a non selective noradrenaline(NA) and 5-hydroxytryptamine (5-HT) reuptake inhibitor, and desipramine,a selective NA reuptake inhibitor, produced local antinociceptiveactions.

Suitable doses of the tricyclic antidepressant adjunctive agents varydue to the wide variations in potency among the various TCAs. The doseis also dependant on the severity of the pain which must be prevented oralleviated, the physical condition of the patient, the relative severityand importance of adverse side effects, and other factors within thejudgment of the physician. Examples of suitable doses and routes ofadministration of tricyclic antidepressant adjunctive agents are listedin Table XVI below:

TABLE XVI TRICYCLIC ANTIDEPRESSANTS TCA Dose Amitriptyline 25-300 mg/dayorally or injection Clomipramine 25-250 mg/day orally Doxepin 25-300mg/day orally Imipramine 25-300 mg/day orally or injection Trimipramine25-300 mg/day orally Amoxapine 50-600 mg/day orally Desipramine 25-300mg/day orally Maprotiline 25-225 mg/day orally Nortriptyline 25-250mg/day orally Protriptyline  10-60 mg/day orally

In embodiments where the present invention contemplates the use of avasodilator, e.g., a nitrate vasodilator. Nitrate vasodilators include,but are not limited to nitrites, organic nitrates, nitroso compounds andany other nitrogen oxide-containing substances.

As capsaicinoids are highly protein bound, vasodilators are useful asadjunctive agents as they facilitate the capsaicinoid being diffusedthroughout the desired site before it has a chance to bind to thetissue.

Organic nitrates and nitrites act on almost all smooth musclestructures, e.g., bronchial, biliary, gastrointestinal tract, uterineand ureteral smooth muscles. Pain and other symptoms associated withincreased pressure can be transiently relieved. For example,administration of a nitrate in a patient with T-tube drainage can reducebiliary pressure and can induce rapid emptying of biliary contents intothe duodenum.

Nitrates, organic nitrates, nitroso compounds, and a variety of othernitrogen oxide-containing compounds work by activating guanylate cyclaseand increasing the synthesis of guanosine 3′,5′-monophosphate (cyclicGMP) in smooth muscle and other tissues. These agents all lead to theformation of nitric oxide (NO). Nitric oxide is a reactive free radicalthat interacts with and activates guanylate cyclase. The interaction ofnitric oxide and guanylate cyclase stimulates cyclic-GMP dependentprotein kinase, which results in the phosphorylation of various proteinsin smooth muscle, which further results in de-phosphorylation of thelight chain of myosin, a protein thought to play an important role inthe contractile process in its phosphorylated form. Analogs ofcyclic-GMP can also relax vascular and bronchial smooth muscle (See:Goodman and Gilman's “The Pharmacological Basis of Therapeutics,” 9thedition, Macmillan Publishing Co., 1996, pp 798-799 and 806-816).

Specific nitrate vasodilator adjunctive agents useful in the presentinvention are also disclosed in detail in The Merck Index, 12^(th)Edition, Merck & Co., Inc nitrate vasodilator agents useful in thepresent invention include, but are not limited to clonitrate, erythrityltetranitrate, isobutyl nitrate, isoidide dinitrite or mononitrite,isomannide dinitrite or mononitrite, isosorbide dinitrate ormononitrate, mononitrate, mannitol hexanitrate, nitroglycerin,pentaeryhtritol tetranitrate, pentaeryhtritol trinitrate or dinitrite ormononitrite, pentrinitrol, propatyl nitrate, sodium nitroprusside,trolnitrate phosphate, 1,3-propane dinitrite, 1,7-heptane dinitrite,cyclohexylmethyl nitrite, 2-phenylethyl nitrite, 3-chloro-2,2dimethylpropyl nitrite, tert-amyl nitrite, 2-methyl-2-hexyl nitrite,hexyl nitrite, 2-methyl-1,3-propane dinitrite, 2,2,dimethyl-1,3-propanedinitrite, 2-methyl-2-propyl-1,3-propane dinitrite, 3-hexyl nitrite,octyl nitrite, 4-methyl-2-pentyl nitrite, 4-methyl-1-pentyl nitrite,2-heptyl nitrite, 3-octyl nitrite, 2-methyl-2-pentyl nitrite,5-methyl-2-hexyl nitrite, 6-methyl-2-heptyl nitrite pharmaceuticallyacceptable salts thereof and mixtures thereof.

Suitable doses of the nitrate vasodilator adjunctive agents vary due tothe wide variations in potency among the various nitrate vasodilators.The dose is also dependant on the severity of the pain which must beprevented or alleviated, the physical condition of the patient, therelative severity and importance of adverse side effects, and otherfactors within the judgment of the physician. In certain embodiments ofthe present invention suitable doses of nitrate vasodilator adjunctiveagents may range from about 0.0001 to 120 mg/kg of body weight per day,more preferably from about 0.01 to about 75 mg/kg and most preferablyfrom about 0.5 to about 30 mg/kg.

In certain embodiments of the present invention, oral doses of thevasodilator adjunctive agents range from about 2.5 to about 300 mg/dayof nitrite, preferably from about 5 to about 160 mg/day.

In certain embodiments, a vasodilator and a vasoconstrictor can be usedas adjunctive therapy for capsaicinoid administration. For example, thecapsaicinoid can be administered with a vasodilator at the intendedsite. To compliment the capsaicinoid therapy, a local anesthetic can beadministered at a distal site to provide a regional block at the site ofcapsaicinoid administration. The vasoconstrictor can be administeredwith the local anesthetic to prolong the duration of effect of the localanesthetic.

In certain other embodiments there is provided a composition comprisinga capsaicinoid and one or more adjunctive agents disclosed herein.

Breakthrough Pain

The term “breakthrough pain” means pain which the patient experiencesdespite the fact that the patient is being or was administered generallyeffective amounts of, e.g., capsaicin. In conjunction with the use ofthe capsaicinoid formulations and methods described herein, it iscontemplated that it is nonetheless possible that the patient willexperience breakthrough pain. For the treatment of breakthrough pain,the individual may be further administered an effective amount of ananalgesic in accordance with the treatment of pain in such situationsperformed by those skilled in the art. The analgesic may be any known tothe person skilled in the art such as those selected from the groupcomprising gold compounds such as sodium aurothiomalate; non-steroidalanti-inflammatory drugs (NSAIDs) such as naproxen, diclofenac,flurbiprofen, ibuprofen ketoprofen, ketorolac, pharmaceuticallyacceptable salts thereof and the like; opioid analgesics such ascodeine, dextropropoxyphene, dihydrocodeine, morphine, diamorphine,hydromorphone, hydrocodone, methadone, pethidine, oxycodone,levorphanol, fentanyl and alfentanil, para-aminophenol derivatives suchas paracetamol, pharmaceutically acceptable salts thereof and the like;and salicylates such as aspirin.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS Example IOsteoarthritis of the Knee Safety Study

The following clinical study was carried out in order to evaluate thesafety, tolerability, systemic pharmacokinetics, and efficacy ofpurified capsaicin administered by intra-articular infiltration togetherwith a local anesthetic administered by intra-articular infiltration insubjects with osteoarthritis of the knee.

The primary objective of the study was to evaluate the safety andtolerability of intra-articular capsaicin, when co-administered withintra-articular local anesthetic, compared to placebo, in subjects withend-stage osteoarthritis of the knee, already scheduled to receive kneereplacements.

Purified capsaicin was supplied in vials containing 5 mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug was stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle was used to dilute the drug to final concentrationsof purified capsaicin, as follows:

TABLE 1 Dose Level Concentration Total Volume of Dose  10 μg  2 μg/mL 5mL 100 μg 20 μg/mL 5 mL 300 μg 60 μg/mL 5 mL

Each vial was used for one infiltration administration only andappropriately labeled. The supplier of the purified capsaicin wasFormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vialswere supplied in bulk to the study center with each vial labeledaccording to the contents of the vial. The Pharmacist/Study Nurse, whoprepared the injection, maintained the investigational product in alockable cabinet at the required temperature, 15-25° C. The study blindwas maintained by the Pharmacist/Study Nurse.

Placebo vehicle for purified capsaicin was supplied in vials containing5 mL. Local anesthetic (Lignocaine 2%) was used for each intra-articularinfiltration.

The study was a single center, randomized, double blind, placebocontrolled, dose ranging Phase 1 study of three dose levels (10 μg, 100μg, or 300 μg) of intra-articularly administered purified capsaicin,when co-administered with intra-articular local anesthetic, in subjectswith osteoarthritis of the knee who were scheduled to undergo total kneereplacement. The doses of purified capsaicin used in this trial werewell below (>100 fold) doses known to be toxic to animals. The study wasdesigned to include 16 evaluation subjects. Sixteen subjects wereenrolled in the study; 12 were treated with ultra-purified capsaicin (4each with 10, 100, and 300 μg doses) and 4 were treated with placebovehicle. Sixteen subjects completed the study.

Patients were treated randomly and in double-blind fashion in fourtreatment groups, with each group having a progressively longer intervalbetween the intra-articular administration of study medication andsubsequent total knee replacement (2, 4, 7, and 14 days). Four subjects,1 in each of the 4 dose groups (placebo, 10 μg, 100 μg, and 300 μg ofcapsaicin), were enrolled in each treatment group. Gross and microscopicpathology analysis was completed for each treatment group before thenext treatment group was treated.

Each subject had 3 study visits: a Screening Day (Day −7 to −1), theTreatment Day (Day 0), and a Post-Treatment Day (scheduled for Day +2,+4, +7, or +14). On the Treatment Day the subject was randomized,pre-treatment evaluation was performed. The patients were brought intothe procedure room, and a VAS pain score was taken (0 mm—no pain, 100mm—extreme pain). Once the patient had marked his or her pain on thecard, he/she was prepped for knee cannulation. Once the cannula wasplaced, the patient received by intra-articular infiltration, 3 mg/kg(maximum dose of 200 mg) of 2% lignocaine into the knee scheduled to bereplaced. This administration of local anesthetic was followed in 10minutes by an intra-articular infiltration of placebo (vehicle) or 10μg, 100 μg, or 300 μg of purified capsaicin diluted with vehicle to atotal volume of 5 mL.

VAS pain scores as well as verbal reports were taken immediatelyfollowing administration, as well as prior to knee replacement surgery.No subjects discontinued from the study due to adverse events.

Immediately following instillation of capsaicin, some patients (0 of 4receiving placebo, 0 of 4 receiving 10 μg capsaicin, 1 of 4 receiving100 μg capsaicin, and 4 of 4 receiving 300 μg capsaicin) reportedtransient burning pain representative of capsaicin injection (onsetwithin a few seconds to minutes and lasting less than one hour). Painwas mild but for some patients, the investigator chose to place icepacks on the treated knee until the pain resolved. In particular, thesubject in the 100 μg dose group and 2 of the subjects in the 300 μgdose group had burning post-administration (hyper) algesic pain alone;two subjects in the 300 μg dose group had burning pain in conjunctionwith other types of post-administration (hyper) algesic pain (1 subjecthad burning and stinging pain and the second subject had burning andtoothache-like pain). All of the episodes of post-administration (hyper)algesia began immediately (within 5 minutes) after administration. Allof these painful episodes were brief: the duration of this pain was 9minutes for the subject in the 100 μg dose group, and 17, 25, 25, and 42minutes for the subjects in the 300 μg dose group. The 4 subjects in the300 μg dose group and 1 subject in the 100 μg dose group requiredintervention for their post-injection (hyper) algesia. For all but 1 ofthese 5 subjects, the only intervention was ice packs. One subject inthe 300 μg dose group was treated with paracetamol; no subjects weretreated with intravenous morphine or granisetron for post-administration(hyper) algesia. Most of the concomitant medications used in the studywere medications taken prior to the study that continued to be takenduring the study. The only concomitant non-drug treatments during thestudy were the ice packs used in the 5 subjects with post-administration(hyper) algesia.

On the Post-Treatment Day, study evaluation was performed followed bythe scheduled knee replacement, with intra-operative bone and softtissue biopsies performed for subsequent examination. For overallefficacy analysis, we chose to exclude the patients who had surgery twodays following administration since analgesia from remaining lignocaineor residual pain from the actual procedure (large volume infiltration)and lysing c-fiber endings could not be excluded (In normal volunteers,a mild “aching” pain is sometimes observed for up to two days followingcapsaicin administration). This therefore left the 3 placebo and 9active patients from the 4 day, 7 day, and 14 day cohorts. Examinationof the VAS scores prior to drug/placebo administration and the day ofsurgery (prior to surgery) showed that pain scores were not reduced inthe placebo group (VAS decreased by only 7±30%), but was reduced in thecapsaicin group (VAS reduced by 62±14%). The changes in VAS score arereported graphically as shown in FIG. 1. The plasma concentration overtime of the three dosage ranges of capsaicin are shown in FIG. 2.

Ten-mL blood samples for subsequent assay of plasma ultra-purifiedcapsaicin concentrations were collected prior to study medicationadministration, at 30 minutes, 1, 2, and 4 hours after study medicationinjection, and immediately prior to the first administration ofpre-operative medications on the Post Treatment Day. The pharmacokineticparameters of Cmax, Tmax, AUC(0−t_(last)) and t½ were evaluated.

In the 10 μg dose group, purified capsaicin plasma concentrations weremeasurable at only 0, 1, or 2 time points; therefore, no pharmacokineticparameters could be estimated for any subject in this dose group. Forthe 3 subjects in each of the 100 μg, and

300 μg dose groups for which pharmacokinetic parameters could beestimated, the magnitude of the Cmax and AUC(0−t_(last)) values wassimilar in the 2 dose groups. Tmax values were 0.5 hr in all subjectsfor which they could be estimated. Terminal exponential half-lives weresimilarly brief in all subjects in both the 100 μg and 300 μg dosegroups.

The AUC(0−t_(last)) values for the subjects in the 100 μg dose group(366.10, 75.19, and 511.21 pg*hr/mL) were similar in magnitude to thevalues for the 300 μg dose group (449.01, 220.42, and 498.83 pg*hr/mL).Similarly, the C_(max) values in the 100 μg dose group (292.06, 79.94,and 538.32 pg/mL) were similar in magnitude to the values in the 300 μgdose group (207.62, 251.42, and 499.88 pg/mL). T_(max) was 0.5 hours inall 6 subjects. The terminal exponential half lives were brief in allsubjects, with values of 0.1498, 1.1488, and 0.1014 hr in the 100 μgdose group and values of 0.3268, 0.2298, and 0.1663 in the 300 μg dosegroup.

The pharmacokinetic conclusions are necessarily limited, because thenumber of timepoints at which plasma concentrations of purifiedcapsaicin was measurable was so limited in these study subjects.However, there was some evidence for a pharmacokinetic dose responseover the 10 μg to 300 μg dose range in that the purified capsaicinplasma concentrations in the 10 μg dose group were clearly lower than ineither the 100 μg or the 300 μg dose groups. However, there was littleevidence for a pharmacokinetic dose response over the 100-300 μg doserange.

Purified capsaicin was well tolerated at all dose levels. There was lowleakage of study drug from the joint space and gross and microscopicpathology was normal. There were no treatment related signs of erythema,edema, or hemorrhage at the site of injection, and no treatment relatedeffects on soft tissue, cartilage, or bone upon histopathologicalexamination. No treatment related systemic side effects were seen, andthere were no treatment related effects on laboratory safety parametersor vital signs. There was no discernable effect on proprioception at theinjected knee in any dose group at any time point.

There was a clear dose response for the incidence of post injectionhyperalgesia. This symptom occurred in 4 subjects in the 300 μg dosegroup, 1 subject in the 100 μg dose group, and no subjects in the 10 μgdose group or placebo. In all but one case, the hyperalgesia wasdescribed as a burning sensation, which developed within five minutes ofinjection and lasted on average less than thirty minutes. In all caseswhere intervention was required, the hyperalgesia was easily andeffectively controlled by the application of ice packs to the knee.

Subjects were asked to rank their level of pain on a visual analoguescale (VAS), anchored by “no pain” on the left and “extreme pain” on theright, prior to receiving the intra-articular dose of purified capsaicinand local anesthetic and then again just prior to administration ofpreoperative medications on the day of knee replacement surgery. Noclear treatment related indication of efficacy was seen at any of thedose levels (10 μg, 100 μg, and 300 μg) of purified capsaicin.

Since intra-articular infiltration of local anesthetic followed byintra-articular infiltration of capsaicin was generally well-tolerated,and the median decreases from baseline to the pre-operative time pointin the VAS for pain at the target knee in all 3 capsaicin dose groupswere all substantially greater that the median change from baseline inthe placebo group, the risk to benefit ratio of this treatment strategyappears favorable. Further studies of this treatment in larger numbersof subjects with osteoarthritis appear warranted.

Example II Osteoarthritis of the Knee Efficacy Study

The following clinical study evaluates the efficacy of purifiedcapsaicin administered by intra-articular infiltration together with alocal anesthetic injected by intra-articular infiltration in subjectswith osteoarthritis of the knee.

The primary objective of the study is to evaluate the efficacy ofintra-articular capsaicin, when co-administered with intra-articularlocal anesthetic, compared to placebo, in subjects with end-stageosteoarthritis of the knee, already scheduled to receive kneereplacements (21 and 42 days after injection of study medication).

Purified capsaicin is supplied in vials containing 5 mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug was stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle is used to dilute the drug to final concentrations ofpurified capsaicin, as follows:

TABLE 2 Dose Level Concentration Total Volume of Dose 1000 μg 200 μg/mL5 mL

Each vial is used for one infiltration administration only andappropriately labeled. The supplier of the purified capsaicin isFormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vialsare supplied in bulk to the study center with each vial labeledaccording to the contents of the vial. The Pharmacist/Study Nurse, whoprepares the injection, maintains the investigational product in alockable cabinet at the required temperature, 15-25° C. The study blindis maintained by the Pharmacist/Study Nurse.

Placebo vehicle for purified capsaicin is supplied in vials containing 5mL. Local anesthetic (Lignocaine 2%) is used for each subacromial bursainfiltration.

The study is a single center, randomized, double blind, placebocontrolled, dose ranging Phase 2 study of capsaicin (1000 μg)administered by intra-articular infiltration, when co-administered withintra-articular local anesthetic, in subjects with osteoarthritis of theknee who are scheduled to undergo total knee replacement from three tosix weeks post study drug administration, wherein the primary endpointis pain reduction at three weeks following study drug administration.

The study is designed to include 12 evaluation subjects (Patientssuffering a defined pain: >40 mm on VAS). Six (6) subjects will betreated with capsaicin 1000 μg and 6 subjects will be treated withplacebo vehicle. Patients are treated randomly and in double-blindfashion. Gross and microscopic pathology analysis are completed for eachtreatment group. Each subject has 3 study visits: a Screening Day (Day−7 to −1), the Treatment Day (Day 0), and a Post-Treatment Day(scheduled for Day +2, +4, +7, or +14). On the Treatment Day the subjectis randomized, pre-treatment evaluation is performed. The patient isbrought into the procedure room, and a VAS pain score is taken (0 mm—nopain, 100 mm—extreme pain). Once the patient marks his or her pain onthe card, he/she is prepped for knee cannulation. Once the cannula isplaced, the patient receives, by intra-articular infiltration, 3 mg/kg(maximum dose of 200 mg) of 2% lignocaine into the knee scheduled to bereplaced. This infiltration of local anesthetic is followed in 10minutes by an intra-articular infiltration of placebo (vehicle) or 1000μg of purified capsaicin diluted with vehicle to a total volume of 5 mL.

VAS pain scores as well as verbal reports are taken immediatelyfollowing administration, as well as prior to knee replacement surgery.On the Post-Treatment Day, a study evaluation is performed followed bythe scheduled knee replacement, with intra-operative bone and softtissue biopsies performed for subsequent examination. For overallefficacy analysis, patients having surgery two days followinginfiltration are excluded since analgesia from remaining lignocaine orresidual pain from the actual procedure (large volume injection) andlysing c-fiber endings is not capable of being excluded.

Changes in NRS (Numerical Rating Scale) pain scores were measured atthree weeks following administration. Final NRS score for placebo=7.30(p=0.05), whereas final NRS score for capsaicin=3.97 (P=0.03) (See FIG.3).

Example III Bunionectomy Efficacy Study

The following study was carried out in order to evaluate the safety,tolerability, systemic pharmacokinetics, and efficacy of intra-operative(infiltration) capsaicin when co-administered with a local anesthetic inpatients scheduled to undergo transpositional osteotomy (bunionectomy).

The primary objective of the study was to evaluate the safety andtolerability of capsaicin, when co-administered by intra-articularinfiltration with a local anesthetic, compared to placebo, in subjectswith hallux valgus deformity, already scheduled to undergotranspositional osteotomy (bunionectomy). The secondary objective of thestudy was to evaluate the safety, tolerability and systemicpharmacokinetics of purified capsaicin following intra-operativeadministration. The primary efficacy endpoint was the proportion ofsubjects in each treatment group requiring opioid analgesia in the first24 hours post-operatively. The proportions were compared amongsttreatment groups using the Cochran-Haenszel test. Secondary efficacy endpoints included: i) proportion of subjects in each treatment grouprequiring opioid analgesia in the first 36 hour period post-operatively(Similarly, the proportions were compared amongst treatment groups usingthe Cochran-Haenszel test); ii) proportion of subjects in each treatmentgroup requiring opioid analgesia in the 10 day period post-operatively(Similarly, the proportions were compared amongst treatment groups usingthe Cochran-Haenszel test); iii) time to first usage of opioid analgesiain each treatment group (a survival analysis approach will be used: theproduct-limit (Kaplan-Meier) method will be applied to time to firstusage of opioid analgesia. The median time to first usage of opioidanalgesia will be estimated in both treatment groups. Pairwisecomparisons will be performed to test for equality of the survivalcurves between the 2 treatment groups using both the log-rank and theWilcoxon test); iv) total usage of analgesia in each treatment group(the total usage of analgesia will be compared by an analysis ofvariance with treatment and center as independent variables. A pairwisecomparison will be performed between the treatment groups); and v) VASassessment of pain at the site of operation in each treatment group (TheVAS score at each time point will be compared by an analysis of variancewith treatment and center as independent variables. A pairwisecomparison will be performed between the treatment groups). Safetyendpoints included: i) laboratory safety parameters; ii) adverse events;and iii) purified capsaicin blood levels. The efficacy analysis wasperformed on the data obtained ten days postoperatively. The safetyanalysis was performed based on the safety data for the entire study,including the 6 week and 12 week follow-up periods. The blind was brokenat the time the efficacy analysis was performed. However, the individualtreatment assignment was available to the statistical analysis grouponly. All other personnel involved in the study, including theInvestigator, study monitor and proprietary staff, remained blindeduntil the entire study was completed.

Purified capsaicin was supplied in vials containing 5 mL of purifiedcapsaicin at a concentrations of 500 μg/mL. Study drug was stored at atemperature between 15° C. and 25° C. Within four hours prior toinjection, vehicle was used to dilute the drug to final concentrationsof purified capsaicin, as follows:

TABLE 3 Dose Level Concentration Total Volume of Dose 1000 μg 250 μg/mL4 mL

Each vial was used for one infiltration administration only andappropriately labeled. The supplier of the purified capsaicin wasFormaTech, Inc., 200 Bullfinch Drive, Andover, Mass. 01810. The vialswere supplied in bulk to the study center with each vial labeledaccording to the contents of the vial. The Pharmacist/Study Nurse, whoprepared the injection, maintained the investigational product in alockable cabinet at the required temperature, 15-25° C. The study blindwas maintained by the Pharmacist/Study Nurse.

Placebo vehicle for purified capsaicin was supplied in vials containing5 mL. Local anesthetic (Lignocaine 2%) was used for each infiltration.

The study was a single center, randomized, double blind, placebocontrolled, Phase II study of the safety and efficacy of intra-operativecapsaicin, when co-administered with local anaesthetic, in subjectsundergoing transpositional first metatarsal osteotomy and fixation forthe correction of hallux valgus deformity. The dose of capsaicin used inthe trial was 1000 μg.

The study was designed to include 40 evaluation subjects. Twenty (20)randomized to the capsaicin treatment group and twenty (20) to theplacebo control group. Each subject had six (6) study visits: aScreening Day (Day −28 to −1), an Operation Day (Day 0), and four (4)Follow-up visits (scheduled for Days 3, 10 and weeks 6 and 12).

On Operation Day (Day 0) the following was performed: a) Pre-operation:Prior to the initiation of an ankle block, inclusion/exclusion criteriaassessment was performed. Eligible subjects were randomized,pre-treatment evaluation was performed, which included laboratory safetyassessments, measurement of vital signs, VAS assessment of pain at thetarget Hallux valgus, blood sample measurement for purified capsaicinconcentration, and review of concomitant medications; b) Operation: Anankle block [lidocaine 0.5% (up to a total of 20 ml)] was initiated bythe investigator to provide surgical anesthesia, and then atranspositional osteotomy of the first metatarsal +/− an Akin osteotomyof the proximal phalanx in accordance with normal practices andprocedures was performed. Immediately prior to wound closure, theInvestigator slowly dripped the study medication (4 mL) from a syringeinto the wound, ensuring even tissue exposure. The wound was then beclosed according to normal practices and procedures.

Post-Operation:

In the 24 hours following administration of study medication, vitalsigns (supine pulse rate and blood pressure) were recorded at 1, 2, 4and 24 hours post administration. VAS assessment of pain at theoperation site was performed at 1, 4, 8, 12 and 24 hours postadministration. In those instances where VAS measurements coincide withblood sampling procedures, the VAS assessment was performed first. Bloodsamples for measurement of capsaicin concentration were obtained at 1,2, and 4 hours post administration. The quantity of each blood samplewas 10 mL. Laboratory safety assessments, e.g., haematology,biochemistry, urinalysis were performed at 24 hours post administration.Adverse events were spontaneously reported by the subject and recorded.Rescue analgesia medication was provided to the subject if required(initially diclofenac 50 mg, repeated at 8 hourly intervals ifnecessary). When diclofenac was judged by the Investigator to provideinadequate pain relief then the subject was provided with alfentanil 1mg, repeated at 6 hourly intervals, if necessary. After discharge fromthe hospital, alfentanil was substituted with co-codamol 30/500 (codeinephosphate 30 mg+paracetamol 500 mg), repeated at 4 hourly intervals whennecessary. Any usage of rescue medication or concomitant medication wasrecorded in the subject's CRF. At 24 hours post administration of studymedication, the subject was discharged from the clinic.

Follow Up:

Follow-up (days 1-10): Upon discharge from the clinic, the subject wasprovided with a diary card for Days 1-10, and asked to record: VASassessment of pain at the operation site, performed each morning; timeand amount of any rescue medication taken by the subject (at any time);usage of concomitant medications (at any time); adverse eventsexperienced by the subject (at any time). Each subject was also be askedto return to the clinic on Day 3 and on Day 10 post-operation. At theseclinic visits the Investigator examined the subject's diary card andresolved any unclear or inconsistent entries. Data from the diary cardwas transcribed to the subject's CRF. The site of the operation wasinspected by the Investigator to confirm that normal wound healing tookplace.

Follow Up (Week 6): The subject was asked to return to the clinic at 6weeks post operation. The site of the operation was inspected by theInvestigator to confirm that normal wound healing is took place. Thesubject was questioned about any adverse events he/she experienced sincethe last clinic visit, and any usage of concomitant medication.

Follow Up (Week 12): The subject was asked to return to the clinic at 12weeks post operation. The site of the operation was inspected by theInvestigator to confirm that normal wound healing is took place. Thesubject was questioned about any adverse events he/she may experiencedsince the last clinic visit, and any usage of concomitant medication.The Investigator discharge the subject from the study.

The results of the bunionectomy study proved that capsaicin administeredat a dose of 1000 μg into the wound prior to wound closure reduced bothpain score as well as the use of rescue as shown in FIGS. 3 and 4.Reduction in rescue was almost always associated with maintenance of VASscore, i.e., the new drug simply substitutes for the old drug (See;Table 4 below):

TABLE 4 Time Placebo purified capsaicin  1 hr  3.3 +/− 2.3 11.1 +/− 7.3  4 hr  3.1 +/− 2.2 10.7 +/− 3.6   8 hr 19.7 +/− 4.9 5.5 +/− 2.3 12 hr28.1 +/− 9.0 8.2 +/− 3.8 24 hr 11.7 +/− 4.6 1.9 +/− 1.0 48 hr 19.3 +/−8.9 5.9 +/− 2.5 72 hr 22.9 +/− 9.9 10.6 +/− 3.5  mean +/− SEM n = 10placebo, n = 11 purified capsaicin P < 0.05 at each time point

Administration of 1000 μg of capsaicin prior to wound closure decreasedopioid rescue. Only 45% of the study subjects randomized to receivecapsaicin required rescue (one subject required rescue at 1 hr, a secondsubject required rescues at 4 hr, a third subject required rescue at 5hr, a fourth subject required rescue at 8 hr, and a fifth subjectrequired rescue at 12 hr; 6 subjects did not rescue in 72 hours (n=11)),whereas 80% of the study subjects randomized to receive placebo requiredrescue (one subject required rescue at 1 hr, a second subject requiredrescue at 2 hr, a third subject required rescue at 6 hr, a fourthsubject required rescue at 8 hr, a fifth subject required rescue at 12hr, a sixth subject required rescue at 14 hr, a seventh and eighthsubject required rescue at 16 hr, and 2 subjects did not require rescuein 72 hours (n=10) P<0.05).

Example IV Median Sternotomy Study

The primary objective of the study is to determine the amount of opioidconsumption and postoperative pain scores following median sternotomyfor patients receiving purified capsaicin by infiltration and/orinjection. Eligible subjects are patients undergoing cardiac, pulmonary,or mediastinal surgery for any indication between the ages of 20-70years. The operation is performed under general anesthesia and areclosely observed in a post-anesthesia care unit as per the practice ofthe institution. The study drug will be administered to the sternaledges, muscles (e.g., muscle edges), bone (e.g., bone edges), andtissues. All patients receive standard of care opioid on demand fortreatment of pain when transferred to the ward. The dose of capsaicin isadministered to the sternal edges, the muscle, the tissues and/or bone.

Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutesbeginning when the patient first is placed in a bedside chair (orambulated) for 24 hours and then every 4 hours while awake untildischarge from the hospital. Patient diaries will be used followingdischarge for a two-week period.

The primary study endpoint is the time to first request of postoperativeopioid. The amount of opioid rescue used is recorded every 24 hours forthe first 2 weeks, patients will complete an opioid-related symptomdistress (SDS) questionnaire.

Example V Laparoscopic Cholecystectomy Study

The primary objective of this study is to evaluate the amount of opioidconsumption and postoperative pain scores following laparoscopiccholecystectomy in patients administered purified capsaicin byinfiltration and/or injection. Study subjects will receive a dose ofpurified capsaicin in proximity to the surgical site.

This study includes 40 patients (20 randomized to receive capsaicinstudy drug and 20 randomized to receive placebo study drug) between theages of 20-60 years old with symptomatic gallstones. The operation isperformed under general anesthesia and the subject is closely observedin a post-anesthesia care unit for up to 24 hours and remains in thehospital (typically for 1 to 5 days). All patients receive standard ofcare opioid on demand for treatment of pain before discharge, and opioid(to be determined) post discharge. Pain is assessed utilizing VAS 100 mmscale—baseline, every 30 minutes till the 2nd postoperative hour thenevery 4 hours the following 12 hours, an at 24 hours and at days 2, 3,4, 5, 6 and 7. Patient diaries are used following discharge. Studysubject will receive a dose of purified capsaicin 1000-3000 μg dividedover the 4 part wounds-infiltrated along the cut muscle edges.

The primary study endpoint is the time to first request of postoperativeanalgesia The amount of opioid rescue is every 24 hours for first 3days, patients complete an opioid-related symptom distress (SDS)questionnaire.

Example VI Knee Replacement Study

The primary objective of the study evaluates the amount of opioidconsumption and postoperative pain scores following knee replacementsurgery for patients receiving administration of purified capsaicin byinfiltration.

This study includes 80 patients (20 patients are randomized to receiveplacebo, 20 randomized to receive capsaicin 300 μg, 20 randomized toreceive capsaicin 1000 μg, and 20 randomized to receive capsaicin 2000μg). Eligible subjects are patients who undergoing knee replacementsurgery between the ages of 20-70 years old.

The knee replacement operation is performed under general anesthesia andis closely observed in a post-anesthesia care unit as per the practiceof the institution. All patients receive standard of care opioid ondemand for treatment of pain once transferred to the ward. The volume ofcapsaicin administered into the wound opening during closure ranges fromabout 5 ml to about 10 ml.

Pain is assessed utilizing VAS 190 mm scale—baseline, every 60 minutesbeginning when the patient first is placed on mechanicalflexion/extension for 24 hours and then every 4 hours while awake untildischarge from the hospital. Patient diaries are used followingdischarge for a two-week period.

Example VII Mastectomy Study

Mastectomy results in significant pain and requires substantial doses ofopioids postoperatively. Analgesic techniques that provide good paincontrol while minimizing opioid side effects are thus highly desirable.The primary objective of the study is to determine the amount of opioidconsumption and postoperative pain scores following mastectomy forpatients receiving capsaicin.

The study includes 80 patients (20 patients are randomized to receiveplacebo, 20 randomized to receive capsaicin 300 μg, 20 randomized toreceive capsaicin 1000 μg, and 20 randomized to receive capsaicin 2000μg). Eligible patients include patients undergoing mastectomy betweenthe ages of 20-70 years old. The operation is performed under generalanesthesia and is closely observed in a post-anesthesia care unit as perthe practice of the institution. All patients receive standard of careopioid on demand for treatment of pain once transferred to the ward.

The dose of study drug is administered by infiltration in a volume fromabout 5 ml to about 10 ml within the wound cavity during closure.

Pain is assessed utilizing VAS 100 mm scale—baseline, every 60 minutesbeginning when the patient first is placed on mechanicalflexion/extension for 24 hours and then every 4 hours while awake untildischarge from the hospital. Patient diaries are used followingdischarge for a two-week period.

The primary endpoint is time to first request of postoperative opioid.Opioid rescue occurs every 24 hours for the first 2 weeks, patientscomplete an opioid-related symptom distress (SDS) questionnaire.

Example VIII

(i) Examples I to VII are repeated and ibuprofen is administered orallyin an amount of 10/mg/kg before, during or after the administration ofthe capsaicinoid in order to decrease the pain and inflammation at thesite of capsaicinoid administration.

(ii) Examples I to VII are repeated and carbamazepine is administeredorally in an amount of 800 mg/day, before, during or after theadministration of the capsaicinoid in order to decrease propagationand/or generate action potentials.

(iii) Examples I to VII are repeated and amitriptyline is administeredorally in an amount of 100 mg/day either before, during or after theadministration of the capsaicinoid in order to diffuse the capsaicinoidthroughout the area.

(iv) Examples I to VII are repeated and epinephrine is administeredparenterally at the site of action either before, during or after theadministration of the capsaicinoid restrict the capsaicinoid at thearea.

(v) Examples I to VII are repeated and isosorbide dinitrite isadministered by injection at the site of administration of thecapsaicinoid either before, during or after the administration of thecapsaicinoid in order to diffuse the capsaicinoid throughout the area.

The invention has been described in an illustrative manner, and it is tobe understood that the particular embodiments of the capsaicinoidformulations and methods of treatment described herein are intended tobe descriptive rather than limiting. Many modifications and variationsof the methodologies and formulations disclosed herein are possible inlight of the above teachings, and such obvious modifications are deemedto be encompassed within the scope of the appended claims.

1. A method for relieving pain at a site in a human or animal in needthereof, comprising: administering at a discrete painful site in a humanor animal in need thereof a single injectable or implantable dose of acapsaicinoid in an amount effective to denervate said discrete sitewithout eliciting an effect outside the discrete location and toattenuate pain emanating from said site, said effective dose being fromabout 1 mcg to about 5000 mcg of capsaicin or a therapeuticallyequivalent dose of a capsaicinoid other than capsaicin; andcoadministering an amount of a tricyclic antidepressant.
 2. The methodof claim 1, wherein the tricyclic antidepressant is in the sameformulation as the capsaicinoid.
 3. The method of claim 1, wherein thetricyclic antidepressant is in a different formulation than thecapsaicinoid.
 4. The method of claim 1, wherein the tricyclicantidepressant is administered by a different route than thecapsaicinoid.
 5. The method of claim 1, wherein the tricyclicantidepressant is administered by the same route as the capsaicinoid. 6.The method of claim 1, wherein the tricyclic antidepressant isadministered orally, via implant, parenterally, sublingually, rectally,topically, or via inhalation.
 7. The method of claim 3, wherein theadministration of the capsaicinoid and the coadministration of thetricyclic antidepressant have overlapping durations of effect.
 8. Themethod of claim 1, wherein the tricyclic antidepressant is selected fromthe group consisting of adinazolam, amitriptyline, amitriptylinoxide,amoxapine, butriptyline, clomipramine, demexiptiline, desipramine,dibenzepin, dimetacrine, dothiepin, doxepin, fluacizine, imipramine,imipramine-oxide, iprindole, lofepramine, maprotiline, melitracen,metapramine, nortriptyline, noxiptilin, opipramol, pizotyline,propizepine, protriptyline, quinupramine, tianeptine, pharmaceuticallyacceptable salts thereof and mixtures thereof.
 9. The method of claim 1,wherein the tricyclic antidepressant is amitriptyline, pharmaceuticallyacceptable salts thereof and mixtures thereof.
 10. The method of claim8, wherein the tricyclic antidepressant is administered orally.
 11. Themethod of claim 8, wherein the tricyclic antidepressant is administeredparenterally.
 12. The method of claim 1, wherein the tricyclicantidepressant is in an effective amount to provide an antinociceptiveeffect.
 13. The method of claim 1, further comprising administering alocal anesthetic to the human or animal.
 14. The method of claim 1,wherein said dose of capsaicin is from about 10 to about 3000 mcg. 15.The method of claim 1, wherein said dose of capsaicin is from about 300to about 1200 mcg.
 16. The method of claim 1, wherein said dose ofcapsaicinoid is administered in a pharmaceutically acceptable vehiclefor injection or implantation.
 17. The method of claim 16, wherein saidpharmaceutically acceptable vehicle is an aqueous vehicle is selectedfrom the group consisting of Sodium Chloride Injection, RingersInjection, Isotonic Dextrose Injection, Sterile Water Injection,Dextrose, Lactated Ringers Injection and any combinations or mixturesthereof. 18-20. (canceled)
 21. A method for attenuating pain at asurgical site or an open wound in a human or animal, comprising:infiltrating a dose of a capsaicinoid in an amount effective todenervate a site selected from a surgical site or an open wound withouteliciting an effect outside the site, said effective dose being fromabout 1 mcg to about 15,000 mcg of capsaicin or a therapeuticallyequivalent dose of a capsaicinoid other than capsaicin; andcoadministering an amount of a tricyclic antidepressant.
 22. The methodof claim 21, wherein the tricyclic antidepressant is in the sameformulation as the capsaicinoid.
 23. The method of claim 21, wherein thetricyclic antidepressant is in a different formulation than thecapsaicinoid. 24-40. (canceled)